Coveted GLP-1 Drugs Show Early Promise in Alzheimer’s

 There may be no hotter trend in biopharma right now than GLP-1 receptor agonists. Currently approved to treat type 2 diabetes and obesity, this drug class has also shown potential in other indications, from nonalcoholic fatty liver disease and cardiovascular disease to addiction, and recent studies suggest it may help tackle another big target—Alzheimer’s disease.

"[GLP-1] does all kinds of things in the body,” Christian Hölscher, co-founder and chief scientific officer at Kariya Pharmaceuticals and a professor of neuroscience at the Henan University of Chinese Medicine in China, told BioSpace. “It’s just a coincidence that they found an effect in diabetes first.” Kariya and other companies are now pursuing the use of these drugs to treat neurodegeneration.

GLP-1 is a hormone that stimulates insulin secretion after eating, enabling a feeling of fullness and triggering cells to take up glucose from the blood. GLP-1 agonists mimic the effects of this hormone, making them an effective treatment for diabetes and obesity. But GLP-1 is also produced in the central nervous system, predominantly in the brainstem, and its receptors are expressed in multiple regions of the brain, including the striatum and nucleus accumbens.

Glucose is the body’s primary energy supplier—and though the brain only makes up only 2% to 3% of the body’s total weight, it consumes about 20% of those energy resources, Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), told BioSpace.

Howard Fillit

“There’s no doubt there’s increasing insulin resistance with aging across the whole body,” he said, meaning cells fail to take up glucose in response to the hormone. “When there’s sub-optimal glucose and highly active neurons have limited access to energy, they dysfunction and ultimately die on a chronic basis.” The most active neurons are in regions of learning and memory, Fillit said, making them more susceptible to glucose deprivation and, ultimately, neurodegeneration.

Recent Research

Alzheimer’s disease is sometimes called type 3 diabetes because insulin resistance is known to be a contributing factor. A review article published in 2022 in Frontiers in Endocrinology posits that drugs that target GLP-1 to treat type 2 diabetes (T2D) could potentially treat Alzheimer’s as well.

GLP-1 receptor agonists have shown the ability to reduce neuroinflammation and oxidative stress—well-recognized contributors to Alzheimer’s disease—and provide neurotrophic effects in animal models of Alzheimer’s, the authors write, while cautioning that this needs to be verified by further clinical trials.

A poster presentation at the 2023 International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PD) highlighted positive results from one such trial, the Phase II ELAD study, which assessed Novo Nordisk’s liraglutide in mild to moderate Alzheimer’s. ADDF, which Fillit said has been “very interested” in this pathway for many years, was involved in funding the trial.

In Alzheimer’s disease, the brain shrinks over time and cells die, Hölscher, a co-author on the poster, told BioSpace. Biomarker analysis of the study showed that this shrinking process was “much reduced, he said. Patients who received liraglutide had slower reduction in MRI volume and cognition compared to placebo, the authors wrote in the poster abstract. Hölscher called the study “a clear proof of concept” that a GLP-1 receptor agonist can help slow Alzheimer’s progression. 

Christian Hölscher

In 2021, Novo Nordisk—which also markets the GLP-1 receptor agonist semaglutide as Rybelsus for T2D—launched two Phase III trials, EVOKE and EVOKE Plus, studying the drug in approximately 3,700 people with early-stage Alzheimer’s disease. In an email sent to BioSpace, a Novo representative said that the trials are ongoing but declined to comment further for this article. The EVOKE trials are expected to be completed in September 2025.

Hölscher noted that drugs like liraglutide and semaglutide were not designed to treat diseases of the brain. “They’re actually designed to stay in the blood, which is good for diabetes but bad for Alzheimer’s because a drug that stays in the blood doesn’t get into the brain.”

At Kariya, Hölscher has designed drugs to be taken up into the brain that he said show much better effects in preclinical studies. The molecules also have a second component: a glucose-dependent insulinotropic polypeptide (GIP), a hormone he said “works hand-in-hand” with GLP-1. This dual mechanism of action is the same as Eli Lilly’s Mounjaro, currently marketed for T2D and being tested for its effect on obesity. Kariya expects to begin a Phase I trial in September.

A Combination Candidate

Hölscher said the biggest barrier to the uptake of GLP-1 as an approach to Alzheimer’s—and other diseases of the brain—is psychological. “When you talk to people who work in Alzheimer’s, they have never heard of GLP-1,” he said. “It’s still amyloid, amyloid, amyloid.” This dilemma also exists in reverse in the diabetes space, where he said researchers “know everything about GLP-1, but they don’t know anything about the brain.” Combined, this makes it difficult to win research dollars, he noted.

But providing that the mechanism continues to bear out in the clinic, there are advantages to GLP-1 drugs over anti-amyloid antibodies, Hölscher said. “We know that the drugs are safe, they’re easy to apply, and you don’t need IV injections as with the antibodies.”  

It also doesn’t need to be one approach or the other. As Fillit noted, GLP-1 drugs would be “very good candidates to be delivered in combination” with an anti-amyloid drug like Eisai and Biogen’s recently approved Leqembi (lecanemab) or Lilly’s investigational donanemab, because there is no overlap in the mechanism of action. 

In its confirmatory trial, Leqembi was shown to reduce clinical decline in mild to moderate Alzheimer’s by 27%, while donanemab reduced decline in early symptomatic Alzheimer’s by up to 36%. While calling these results “meaningful” and “a big breakthrough,” Fillit said it is obviously not enough. “We want to get to 100% slowing and even prevention,” he said.

https://www.biospace.com/article/coveted-glp-1-drugs-show-early-promise-in-alzheimer-s-disease-/

Jill Biden tests positive for COVID-19 for second time

First lady Jill Biden has tested positive for COVID-19, according to a statement from her office on Monday. President Biden tested negative for the virus.

"This evening, the First Lady tested positive for COVID-19," the statement reads. "She is currently experiencing only mild symptoms. She will remain at their home in Rehoboth Beach, Delaware."

US first lady Jill Biden speaks during a panel on cancer during a visit to the Mays Cancer Center, February 23, 2022, in San Antonio, Texas.  (Photo by SERGIO FLORES/AFP via Getty Images)

First lady Jill Biden has tested positive for COVID, according to a statement from her office on Monday. (AP Photo / Andrew Harnik / File)

The first lady is double-vaccinated, twice boosted, according to a statement from her communications director last year.

The last time the 72-year-old tested positive for the virus was in August 2022. At the time, she was staying at a private residence in South Carolina.

"Following the First Lady's positive test for COVID-19, President Biden was administered a COVID test this evening," White House Press Secretary Karine Jean-Pierre said. "The President tested negative. The President will test at a regular cadence this week and monitor for symptoms."

The announcement comes amid rising COVID cases and hospitalizations throughout the country as several hospital systems have reinstated mask-wearing requirements for patients and staff.

https://www.foxnews.com/politics/first-lady-jill-biden-tests-positive-covid-second-time

"Unprecedented Levels" Of Theft In DC Forces Supermarket Chain To Remove Name-Brand Items

 Walmart, Target, Kohl's, Foot Locker, Dick's Sporting Goods, and Dollar Tree, to name a few, have all raised concerns about out-of-control thefts in their stores nationwide. The latest is supermarket chain Giant Food, which warned about "unprecedented levels" of "shrink" - the loss of inventory due to circumstances such as retail theft - at one of its stores in Washington, DC. 

NBC Washington said the Giant Food, located at 1535 Alabama Ave SE, has already warned if rampant shoplifting continues, the supermarket will have to close its doors.

The Giant on Alabama Avenue SE is the only full-service supermarket in the area, and if it closes, it will create a food desert in Southeast DC. Instead of closing, it seems the grocery chain has come up with a solution:

In a statement, Giant said it plans to remove national brand health and beauty care items and replace them with private label brands where possible. The new policy aims to reduce "unprecedented levels" of theft and make the store safer for shoppers and employees. 

"None of the tactics we deploy is the ultimate solution to the problem we face, but we continue to invest in efforts that will improve safety for our associates and customers and reduce theft," part of the statement read. --NBC Washington

Replacing brand name items, such as Tide, Colgate, or Advil, with only private label products is a last-ditch effort to prevent the store from closing. 

DC's failed progressive social justice reform policies have only emboldened criminals, as AP News warned in July: "Violent crime is rising sharply, fueled by more homicides and carjackings." 

Major corporations who funded the 'defund the police' movement during the Covid era are getting what they deserve: A surge in thefts as soft on crime Democrats in control of many of the nation's cities have only sparked a theft and violent crime wave. 

Retailers sounded the alarm on the theft wave this past earnings season. The number of times CEOs mentioned "shrink" on earnings calls soared to a record high.  

A new report last week drew a Mexican cartel connection in America's retail theft epidemic that cost companies like Walmart, Target, Kohl's, Home Depot, and Foot Locker, among others, tens of billions of dollars last year. Yet another failed Democrat policy to leave borders open. 

 Open borders are not so great after all... It's time to reinforce law and order in the nation or face out-of-control theft waves now making it to suburbia. 

https://www.zerohedge.com/markets/unprecedented-levels-theft-nations-capital-force-supermarket-chain-remove-name-brand-items

'Raise pension contributions to combat UK capital market decline, says think-tank'

 Higher minimum contributions to pension schemes and turning the regulatory screw would help plug shortfalls in retirement income and reverse shrinkage in Britain's capital market, think-tank New Financial said in a report on Tuesday.

A welter of regulatory reforms to bolster London's capital market and boost the flow of money from pensions into investments is a good start, but more is needed to avoid pensioners having too little to live on, said New Financial CEO William Wright.

"This isn't something that we can keep kicking down the road," Wright told reporters.

The report, written in partnership with Citi bank and abrdn asset management, said there is a "parallel crisis" in Britain's pensions and capital market as too little investment flows into UK-based companies and asset managers play safe with government bonds.

"I would wonder if there's something in the Consumer Duty that says there's something about having too much money in a bank account when you don't need it, you should be putting money into something that is better than that," abrdn chair Douglas Flint said.

Regulator the Financial Conduct Authority's Consumer Duty introduced in July requires financial firms to ensure that customers are getting fair value on their investments, and to point out better deals where available.

The report said an employee currently has to contribute a minimum of 8% of earnings to a defined contribution (DC) pension scheme, a "woefully inadequate" level.

This fails to build a big enough pool of money that allows more investment in riskier assets like start-up companies and infrastructure, and reverse a shrinkage in listings.

The median DC pension pot for people aged 55 to 65 is just 35,000 pounds ($44,177), giving an annual pension of 1,750 pounds, meaning a social security safety net is often needed.

"You have to have a glidepath to getting to 15% to 16%. The big issue is the contribution rate," Flint said.

The report rejects mandating pension funds to invest in certain assets, but notes that 48 billion pounds in net tax relief on pension contribution in 2021 alone means there should be a "social contract" to create some form of "quid pro quo" from the sector.

https://www.yahoo.com/lifestyle/raise-pension-contributions-combat-uk-234556413.html

Thoma Bravo Nears Deal for NextGen Healthcare

 Thoma Bravo is in advanced talks to buy software company NextGen Healthcare Inc., according to people familiar with the matter. 

The private equity firm could announce a deal as soon as this week for NextGen, said the people, who asked to not be identified because the matter isn’t public. No final decision has been made and discussions could fall through, the people added. 

Representatives for Thoma Bravo and NextGen didn’t immediately respond to requests for comment. 

NextGen, a health-care information technology company, rose 6.2% to close at $19.33 in New York trading Friday, giving it a market value of about $1.3 billion. 

Based in Atlanta, NextGen provides cloud-based technology services to outpatient health-care providers, according to its annual report. 

Led by Managing Partner Orlando Bravo, Thoma Bravo is one of private equity’s most active technology investors. The firm agreed in June to sell Adenza to Nasdaq Inc. for $10.5 billion. 

https://www.bnnbloomberg.ca/thoma-bravo-nears-deal-for-nextgen-healthcare-1.1967045

Disease-X Is A High-Return Business Strategy

 by David Bell via The Brownstone Institute,

Fearistan, having done very well economically and provided its citizens a long lifespan, noticed that people were still occasionally dying in road accidents. Fearistanis were wealthy and really liked the freedom to travel. While road deaths were uncommon, any unnecessary death surely seemed worth avoiding.

The road-building industry, working closely with government, came up with the idea of building 6-lane highways between cities. Soon the big cities were all connected, and experts from the University of Transport proved that the new highways had a 7 percent lower accident rate than normal roads. University modelers predicted that if 6-lane highways were built between every town in Fearistan, they would save thousands of lives. Experts predicted that they would even save more lives than were actually dying on the existing roads.

The country followed the experts (they were, after all, renowned for building roads) and invested in 6-lane highways everywhere. While the country exhausted itself and most people could not afford to drive their cars anymore, they were rightly grateful that the road-builders were saving them. The near empty roads were now almost completely accident-free, proving the experts right.

Eventually, the road-building industry faced a dilemma; they were running out of towns to which roads could be built. This was not what their investors needed. Then the road regulator and the road-builders met and identified an urgent need to build roads to towns that did not yet exist. Fearistan had vast areas of empty desert that were completely open to town-building. When such towns were eventually built, experts predicted an inevitable and devastating tsunami of road accidents. This would return Fearistan to the total carnage from which they had so narrowly escaped years before. The new Town-X roads (as they termed them) were brilliant examples of high-tech road construction. And everyone could see how important this work was, to keep the public safe. 

In public health, we follow a similarly important business model. We call it ‘Disease-X.’

Understanding pandemic risk from infectious disease

Humans suffered for millennia from pandemics or ‘plagues.’ These killed up to a third of some populations. While causes in some cases remain unclear, such as the Athenian plague of 430 BC, the major plagues since Medieval times were mostly bacterial; particularly bubonic plague, cholera, and typhus. 

Bacterial pandemics ceased in late 19th century Europe with improved sanitation, and elsewhere after the addition of antibiotics. Most deaths from the pre-antibiotic Spanish flu outbreak in the early 20th century are also thought to be untreated secondary bacterial pneumonia. Cholera remains an intermittent marker of extreme poverty and social disruption, whilst most deaths from malaria, tuberculosis, and HIV/AIDS are associated with poverty, which restricts access to effective treatment.

When indigenous populations long separated from the bulk of humanity encountered carriers of smallpox and measles, the effects were also devastating. Having no inherited immunity, whole populations were decimated, particularly in the Americas, Pacific Islands, and Australia. 

Now the world is connected, and such mass death events don’t occur. Connectedness can be a strong defense against pandemics, contrary to what Disease X proponents claim, through its role in supporting early-age immunity and frequent boosting.

These realities reflect orthodox public health but are poorly compatible with current business models. They are, therefore, increasingly ignored.

A century of safety

The past hundred years have seen two significant natural influenza pandemic events (in 1957-8 and 1968-9) and one major coronavirus outbreak (Covid-19) that appears to have arisen from gain-of-function research in a lab. The influenza outbreaks each killed less than currently die annually from tuberculosis, while the coronavirus outbreak was associated with mortality at average age above 75 years, with roughly 1.5 people per thousand dying globally.

While the media fusses about other outbreaks, they have actually been relatively small events. SARS-1 in 2003 killed about 800 people worldwide, or less than half the number of children that die every single day from malaria. MERS killed about 850 people, and the West African Ebola outbreak killed about 11,300. Context here is important; tuberculosis kills over 1.5 million people every year while malaria kills over half a million children, and over 600,000 people die of cancer each year in the United States alone. SARS-1, MERS and Ebola may gain more media coverage than tuberculosis, but this is unrelated to actual risk.

Why are we living longer?

The reason behind increasing human lifespans is frequently forgotten, or ignored. As medical students were once taught, advancements came primarily through improved sanitation, better living conditions, better nutrition, and antibiotics; the same changes responsible for the reduction in pandemics. Vaccines came after most improvement had already occurred (with a few exceptions such as smallpox).

While vaccines do remain an important addition, they are also of particular importance to pharmaceutical companies. They can be mandated, and together with the constant birth of children this provides a continuing, predictable, and profitable market. This is not an anti-vaccine statement. It is just a statement of fact. Facts are what health policy should be based on.

So, we can be confident that, barring an intentional or accidental release of a pathogen engineered by humans, it is highly unlikely that a Medieval-style outbreak will affect anyone currently living. While poverty will reduce life expectancy, it will remain relatively high in wealthier countries. However, we can also be very confident that those half-million young children will die of malaria next year and that 1.5 million people, many of them children and young adults, will die of tuberculosis. 

Over 300,000 women in low-income countries will also die agonizing deaths from cervical cancer because they cannot access cheap screening. We know this, because it happens every year – it is what international public health, particularly the World Health Organization (WHO), was supposed to prioritize.

The ability to monetize an illusion

The Covid-19 response demonstrated how the sponsors of international public health institutions have found a way to monetize public health. This business model involves promoting abnormal responses to relatively normal viruses. It employs behavioral psychology and media campaigns to instill inappropriate fear into the public, then ‘locking them down’ – prison terminology before 2020. The public may then regain a degree of freedom (e.g., fly to visit a dying relative, or work) if they agree to take a vaccine, which in turn directly benefits the original sponsors of the scheme. The heavy public investment in Covid-19 mRNA vaccine development enabled pharmaceutical companies and their investors to reap unprecedented returns.

The major public-private partnership for vaccine development for pandemics, CEPI (inaugurated at the World Economic Forum in 2017), states that “The threat of Disease-X infecting the human population, and spreading quickly around the world, is greater than ever before.” 

Health practitioners are quite susceptible to this propaganda (they are only human). Many also seek income from investments and patents from technologies that may help lock others down or make vaccine production quicker and cheaper. Basing their salaries and careers on loyalty to this pandemic industry, they join in vilifying and scapegoating those who speak against it. Shielded by their sponsors’ ‘greater threat than ever before’ claims, they can blind themselves to the major causes of ill health and act as if only pandemic risk matters.

Why not rely on existing threats?

Despite current efforts with yet another variant, Covid-19 is losing its ability to scare. Sustained fear is necessary for politicians in penetrated governments (as Klaus Schwab of the World Economic Forum notes) to provide this support. This business paradigm requires a continuing target. 

The overall aim is for the public to think that only a corporate authoritarian (fascist) nanny-state can save them from a continuing threat.

Major natural outbreaks being rare, and lab escapes also infrequent, Disease-X fills this need. It provides the material for the media and politicians to work with between variant or monkeypox events.

Where to from here?

For the public, diversion of resources to fairyland diseases will increase mortality by diverting funding for real threats and productive areas of investment. Of course, if increasing lab leaks of engineered pathogens are expected from ongoing and future research, that would be different. But then this would have to be explained plainly and transparently, and prevention may be more effective than a very expensive cure.

Disease-X is a business strategy, dependent on a series of fallacies, dressed up as an altruistic concern for human welfare. Embraced by powerful people, the world they move in accepts amoral practice in public health as a legitimate path to their version of success. 

If our primary aim is to channel taxpayer funding to development of biotechnologies that the public can then be mandated to buy, to their own detriment but at great benefit to the developers, then Disease-X is the road forward. This market model ensures that a relative few can concentrate wealth gained from the many, at virtually no risk to themselves. The public must decide whether they want to keep their part of this highly abusive bargain.

https://www.zerohedge.com/medical/disease-x-high-return-business-strategy

Calcium 'sparks' that can contribute to arrhythmia

 A team of UC Davis and University of Oxford researchers have developed an innovative tool: SparkMaster 2. The open-source software allows scientists to analyze normal and abnormal calcium signals in cells automatically.

Calcium is a key signaling molecule in all cells, including muscles like the heart. The new software enables the automatic analysis of distinct patterns of calcium release in cells. This includes calcium "sparks," microscopic releases of calcium within cardiac cells associated with irregular heartbeats, also known as arrhythmia.

A research article demonstrating the capabilities of SparkMaster 2 was published in Circulation Research.

Jakub Tomek, the first author of the research article, is a Sir Henry Wellcome Fellow in the Department of Physiology, Anatomy and Genetics at the University of Oxford. He spent his fellowship year at UC Davis, working with Distinguished Professor Donald M. Bers.

"It was great to present SparkMaster 2 at recent conferences and see the enthusiastic response. I felt it would be an outlier and that few people would care. But many people were excited about having a new analysis tool that overcomes many of the limitations they have experienced with prior tools," Tomek said.

Fellowship at UC Davis leads to updated tool

Problems with how and when calcium is released by cells can have an impact on a range of diseases, including arrhythmia and hypertension. To understand the mechanisms behind these diseases, researchers use fluorescent calcium indicators and microscopic imaging that can measure the calcium changes at the cellular level.

However, the resulting data files are large and challenging to analyze by hand, so customized software analysis tools are essential.

At the Bers Lab at UC Davis, Tomek discussed analysis tools with Christopher Y. Ko, an assistant project scientist. They identified the need for better, more user-friendly software, which led to the development of SparkMaster 2.

The new tool builds upon the success of SparkMaster, which was released in 2007 by Bers and Eckard Picht. Picht is a physician-scientist who worked with Bers, first at Loyola University Chicago and then for a few years at UC Davis. At the time, there was no user-friendly free software that could analyze calcium sparks -- a crucial part of their research -- so they developed one.

To create the new software, SparkMaster 2, Tomek worked with Bers, Ko, Manuel F. Navedo and Madeline Nieves-Cintron in the Department of Pharmacology at the UC Davis School of Medicine.

Although much of the new interface resembles the original SparkMaster, they started from scratch for the programming. Using Python, an open-source programming language that has grown in popularity, they were able to utilize many existing tools and libraries to create the unique features they wanted.

They ended up with software that can analyze calcium sparks recorded using different microscopy approaches and from cells from different tissues and genetically modified mice. Some key features of the new version include:

• improved user interface
• higher accuracy at identifying calcium release events than previous tools
• ability to identify multiple types of calcium-release events
• ability to accurately split and analyze individual sparks within spark clusters

"SparkMaster 2 is even easier to use and is much more powerful in the variety of event types it can analyze quantitatively -- sparks, waves, mini-waves and latencies. And it has higher accuracy and sensitivity, resulting in fewer missed events and fewer erroneous positives," Bers said.

Bers anticipates the primary users of the software will be scientists who study calcium in muscle. "But it may be useful for researchers who study other cell types, such as neurons, that exhibit local calcium events that are important in regulating cellular function," Bers said.

Ko, who is a co-developer of the new tool, is also interested in the broader research applications for the new software.

"I'm particularly excited about the new scientific questions that SparkMaster 2 will enable the biomedical research community to answer and, in turn, the ability to more completely and accurately understand the biology that underlies human physiology in health and disease," Ko said.

Additional authors on the paper include Nieves-Cintron and Navedo from UC Davis. They were instrumental in demonstrating how the software can be used outside cardiac research, and across distinct cell types, showing its wide range of possible uses.

Journal Reference:

1. Jakub Tomek, Madeline Nieves-Cintron, Manuel F. Navedo, Christopher Y. Ko, Donald M. Bers. SparkMaster 2: A New Software for Automatic Analysis of Calcium Spark Data. Circulation Research, 2023; 133 (6): 450 DOI: 10.1161/CIRCRESAHA.123.322847

https://www.sciencedaily.com/releases/2023/09/230901201952.htm