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Fixing the Aging Brain

The number one thing most people fear as they age is developing dementia. As the world’s population becomes increasingly older, this is a growing public…

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The number one thing most people fear as they age is developing dementia. As the world’s population becomes increasingly older, this is a growing public health issue too. The World Health Organization estimates that 55 million people already have dementia worldwide. With a global market estimated to reach $13 billion over the next few years, drug developers are eager to get a bite of this market, but until recently, it has proved to be one of the toughest fields to enter.

Now, Leqembi, the first drug that treats Alzheimer’s underlying biology is finally fully approved and being covered by Medicare. Alzheimer’s is the leading cause of dementia. There are also new data sources, and insights on root causes of this and other forms of cognitive decline, as well as new tests to guide treatment. Plus, we are hearing lots of discussion about whether prominent elderly political figures, such as U.S. president Biden and former U.S. president Trump, have the mental stamina required for public offices.

The aging brain is in the spotlight.

Studying the human brain is always a challenge, and in this case there have been a few detours. “Mouse models just recapitulate certain phenotypes, but even though it looks like Alzheimer’s it really isn’t a good model,” says Ulrich Hengst, PhD, associate professor of Pathology and Cell Biology at Columbia University’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain.

As a result, it has been extremely difficult to develop drugs for this condition. In the last decade, more than 200 drug discovery programs for Alzheimer’s have failed or been abandoned. The field was a wasteland, and still researchers persisted.

So, how did things change and start to look more hopeful?

Rethinking the amyloid hypothesis

An important step forward, says Hengst, has been a shift in how we think about the famous “amyloid hypothesis,” which is about 30 years old. This hypothesis suggested the accumulation of the peptide amyloid beta, 10-20 years before there are signs of the disease, was the starting point of the disease. After all, this leads to harmful plaques that are a hallmark of Alzheimer’s. Mopping up that molecule, the reasoning went, should help slow or even reverse cognitive decline.

“The idea used to be that it was a straight line from amyloid beta to neurodegeneration,” Hengst says. “But now we think its much more complicated than that, with on and off ramps,”

Even if clearing amyloid beta was sufficient, it occurs in different ways, Hengst points out—inside and outside of cells. “We had to figure out what amyloid to target and which are the best antibodies” he says. Also, importantly, amyloid beta is more easily cleared from the rodent brain than humans.

Seth Gale
co-director, Brain Health Program Division of Cognitive and Behavioral Neurology
assistant professor of Neurology
Harvard Medical School Neurology

“How the monoclonal binds and what it binds to is key,” says Seth Alan Gale, MD, co-director of the Brain Health Program at Harvard Medical School. What triggers the cascade is still not known, but it’s clear it involves more than amyloid beta. “From lab research and studying families with genetic mutations we know they first develop amyloid beta, but there are also tau tangles and inflammation,” he adds.

Both Hengst and Gale agree that Leqembi, (Biogen and Eisai’s lecanemab-irmb), is not the breakthrough drug we were waiting for. But it is the first fully approved treatment shown to reduce the rate of detectable Alzheimer’s progression and slow cognitive and functional decline.

For one thing, Hengst says, the drug only works in about 30% of patients: “It’s a case where the glass is half full and half empty.”

Says Gale, “The cognitive benefits of the drug are modest, sometimes it is hard to even see them. It’s just a beginning. It proves there is something we can do with amyloid beta.”

They both anticipate a future where a combination of therapies will target more than amyloid beta. They may even personalized, according to specific mutations or other factors.

New data and approaches

Among the new targets for Alzheimer’s drugs are tau, apolipoprotein E (APOE)/lipids and lipoprotein receptors, neurotransmitter receptors, neurogenesis, inflammation, growth factors, and more. But how will drug developers pick among these targets?

Hengst’s group recently identified a new amyloid beta-triggered pathway in Alzheimer’s that points to a potential drug for the disease. The team used datasets and a novel chemogenetic method that resolves the genomic binding profile of dimeric transcription factors.

They showed amyloid beta promotes the formation of pathological CREB3L2-ATF4 transcription factor heterodimers in neurons. This process activates a transcription network that interacts with roughly half of the genes differentially expressed in Alzheimer’s. Further, the team determined that the drug dovitinib, Allarity’s pan-tyrosine kinase inhibitor, could be a candidate against this target.

Another recent study, from INSERM, involved a two-stage genome-wide association study of more than 110,000 people with Alzheimer’s. This team found 75 risk loci, 42 of which were new. Genome-wide summary statistics were deposited to the European Bioinformatics Institute GWAS Catalog.

Tony Wyss-Coray
Tony Wyss-Coray, PhD
professor of neurology and neurological sciences
Stanford Medicine

Another new tool is a spatiotemporal RNA sequencing atlas of the mouse brain recently constructed by the lab of Tony Wyss-Coray, PhD, professor of Neurology and Neurological Sciences, and director of the Phil and Penny Knight Initiative for Brain Resilience at Stanford University. The team looked at 1,076 samples from 15 regions across seven ages and two rejuvenation interventions. They are planning to repeat this with human samples.

But the mouse data has given them a good start. “We made a number of discoveries,” says Wyss-Coray. “For one thing, these regions do not age in synchrony, a gene’s activity can go up several fold in one region but not in another. Also, the white matter is the connection between regions that show most of the changes.”

There are also other causes than Alzheimer’s of cognitive decline, such as vascular disease.

Women, for example, are more likely than men to develop dementia, and that has long been assumed that to be due to the fact that they live longer. But new evidence suggests that pregnancy complications may also lead to higher risk of earlier cognitive decline.

Among these findings, a Swedish team recently found that risk of later dementia increases for women who experienced pregnancy-induced hypertension, spontaneous preterm labor, or preterm rupture of membranes (placental bed disorders). Such disorders, the team concluded, are associated with vascular dementia even after adjusting for cardiovascular disease.

New tests and clinical protocols are being developed to protect pregnant women from these conditions.

Keys to graceful aging

Lifestyle also has a role in cognitive decline. “It seems to have modest benefits, but people who adopt healthy lifestyles can modify their risk of dementia,” says Gale. He thinks that along with new therapies, lifestyle changes will be a help.

There is also widespread agreement that earlier detection could help clinical care and drug development. So, a priority is improving diagnosis of Alzheimer’s and other conditions that affect cognitive function.

Valentina Garibotto
Valentina Garibotto
Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Geneva University Neurocenter
Faculty of Medicine, University of Geneva

“Amyloid deposition is not strongly correlated with cognition, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss,” says Valentina Garibotto, of the Laboratory of Neuroimaging and Innovative Molecular Tracers at Geneva University.

She points out that better selection of patients is crucial to optimal trial design and she sees the measurement of Tau as being an important step forward. “Tau is routinely measured in CSF, and several new blood tests are in development to measure phosphorylated tau,” she says.

Only one tau PET radiopharmaceutical, [18F]-flortaucipir, has FDA approval, also though this test is routinely used in clinical trials. In fact, Garibotto says, “Crucially, participants in TRAILBLAZER-ALZ 2 [a trial of Eli Lilly’s donanemab] were stratified by their level of tau, as assessed by tau PET,

Gale notes that new diagnostic criteria will soon be available from the National Institute on Aging and the Alzheimer’s Association (NIA-AA) The criteria were posted for final review at the end of August this year. Medicare is also planning to expand its coverage of PET scans, which are one of the best means of detecting amyloid beta on the brain.

Former president Trump famously said that he had to remember the words: “Person. Woman. Man. Camera. TV,” as part of a test to demonstrate his mental acuity. The test, the Montreal Cognitive Assessment, is designed to detect signs of Alzheimer’s or other types of dementia.

With advances in precision medicine, we are poised to have much more sophisticated tests in hand. That should make old age much easier for many people.

 

Read More

Atlas of the aging mouse brain reveals white matter as vulnerable fociCell, 2023.

Can precision pregnancy save more mothers?Inside Precision Medicine, 2023.

CREB3L2-ATF4 heterodimerization defines a transcriptional hub of Alzheimer’s disease gene expression linked to neuropathology—Science Advances, 2023.

New insights into the genetic etiology of Alzheimer’s disease and related dementiasNature Genetics, 2022.

Montreal Cognitive Assessment (MoCA) website, 2023.

Person. Woman. Man. Camera. TV,’ didn’t mean what Trump hoped it didThe New York Times, 2020.

Prior placental bed disorders and later dementia: a retrospective Swedish register-based cohort studyBJOG, 2020.

Reasons for failed trials of disease-modifying treatments for Alzheimer Disease and their contribution in recent research—Biomedicines, 2019.

The Alzheimer’s disease drug development landscape—BMC. 2021.

The impact of tau deposition and hypometabolism on cognitive impairment and longitudinal cognitive declineAlzheimer’s & Dementia, 2023.

 

Malorye Branca is a contributing editor at Inside Precision Medicine and a freelance medical science journalist. She has written hundreds of articles, as well as managed and launched health and science magazines, newsletters, and market research report businesses. She has also co-authored two books: “Moneyball Medicine” and “Walmart’s Second Opinion.”

The post Fixing the Aging Brain appeared first on Inside Precision Medicine.

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Four burning questions about the future of the $16.5B Novo-Catalent deal

To build or to buy? That’s a classic question for pharma boardrooms, and Novo Nordisk is going with both.
Beyond spending billions of dollars to expand…

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To build or to buy? That’s a classic question for pharma boardrooms, and Novo Nordisk is going with both.

Beyond spending billions of dollars to expand its own production capacity for its weight loss drugs, the Danish drugmaker said Monday it will pay $11 billion to acquire three manufacturing plants from Catalent. It’s part of a broader $16.5 billion deal with Novo Holdings, the investment arm of the pharma’s parent group, which agreed to acquire the contract manufacturer and take it private.

It’s a big deal for all parties, with potential ripple effects across the biotech ecosystem. Here’s a look at some of the most pressing questions to watch after Monday’s announcement.

Why did Novo do this?

Novo Holdings isn’t the most obvious buyer for Catalent, particularly after last year’s on-and-off M&A interest from the serial acquirer Danaher. But the deal could benefit both Novo Holdings and Novo Nordisk.

Novo Nordisk’s biggest challenge has been simply making enough of the weight loss drug Wegovy and diabetes therapy Ozempic. On last week’s earnings call, Novo Nordisk CEO Lars Fruergaard Jørgensen said the company isn’t constrained by capital in its efforts to boost manufacturing. Rather, the main challenge is the limited amount of capabilities out there, he said.

“Most pharmaceutical companies in the world would be shopping among the same manufacturers,” he said. “There’s not an unlimited amount of machinery and people to build it.”

While Novo was already one of Catalent’s major customers, the manufacturer has been hamstrung by its own balance sheet. With roughly $5 billion in debt on its books, it’s had to juggle paying down debt with sufficiently investing in its facilities. That’s been particularly challenging in keeping pace with soaring demand for GLP-1 drugs.

Novo, on the other hand, has the balance sheet to funnel as much money as needed into the plants in Italy, Belgium, and Indiana. It’s also struggled to make enough of its popular GLP-1 drugs to meet their soaring demand, with documented shortages of both Ozempic and Wegovy.

The impact won’t be immediate. The parties expect the deal to close near the end of 2024. Novo Nordisk said it expects the three new sites to “gradually increase Novo Nordisk’s filling capacity from 2026 and onwards.”

As for the rest of Catalent — nearly 50 other sites employing thousands of workers — Novo Holdings will take control. The group previously acquired Altasciences in 2021 and Ritedose in 2022, so the Catalent deal builds on a core investing interest in biopharma services, Novo Holdings CEO Kasim Kutay told Endpoints News.

Kasim Kutay

When asked about possible site closures or layoffs, Kutay said the team hasn’t thought about that.

“That’s not our track record. Our track record is to invest in quality businesses and help them grow,” he said. “There’s always stuff to do with any asset you own, but we haven’t bought this company to do some of the stuff you’re talking about.”

What does it mean for Catalent’s customers? 

Until the deal closes, Catalent will operate as a standalone business. After it closes, Novo Nordisk said it will honor its customer obligations at the three sites, a spokesperson said. But they didn’t answer a question about what happens when those contracts expire.

The wrinkle is the long-term future of the three plants that Novo Nordisk is paying for. Those sites don’t exclusively pump out Wegovy, but that could be the logical long-term aim for the Danish drugmaker.

The ideal scenario is that pricing and timelines remain the same for customers, said Nicole Paulk, CEO of the gene therapy startup Siren Biotechnology.

Nicole Paulk

“The name of the group that you’re going to send your check to is now going to be Novo Holdings instead of Catalent, but otherwise everything remains the same,” Paulk told Endpoints. “That’s the best-case scenario.”

In a worst case, Paulk said she feared the new owners could wind up closing sites or laying off Catalent groups. That could create some uncertainty for customers looking for a long-term manufacturing partner.

Are shareholders and regulators happy? 

The pandemic was a wild ride for Catalent’s stock, with shares surging from about $40 to $140 and then crashing back to earth. The $63.50 share price for the takeover is a happy ending depending on the investor.

On that point, the investing giant Elliott Investment Management is satisfied. Marc Steinberg, a partner at Elliott, called the agreement “an outstanding outcome” that “clearly maximizes value for Catalent stockholders” in a statement.

Elliott helped kick off a strategic review last August that culminated in the sale agreement. Compared to Catalent’s stock price before that review started, the deal pays a nearly 40% premium.

Alessandro Maselli

But this is hardly a victory lap for CEO Alessandro Maselli, who took over in July 2022 when Catalent’s stock price was north of $100. Novo’s takeover is a tacit acknowledgment that Maselli could never fully right the ship, as operational problems plagued the company throughout 2023 while it was limited by its debt.

Additional regulatory filings in the next few weeks could give insight into just how competitive the sale process was. William Blair analysts said they don’t expect a competing bidder “given the organic investments already being pursued at other leading CDMOs and the breadth and scale of Catalent’s operations.”

The Blair analysts also noted the companies likely “expect to spend some time educating relevant government agencies” about the deal, given the lengthy closing timeline. Given Novo Nordisk’s ascent — it’s now one of Europe’s most valuable companies — paired with the limited number of large contract manufacturers, antitrust regulators could be interested in taking a close look.

Are Catalent’s problems finally a thing of the past?

Catalent ran into a mix of financial and operational problems over the past year that played no small part in attracting the interest of an activist like Elliott.

Now with a deal in place, how quickly can Novo rectify those problems? Some of the challenges were driven by the demands of being a publicly traded company, like failing to meet investors’ revenue expectations or even filing earnings reports on time.

But Catalent also struggled with its business at times, with a range of manufacturing delays, inspection reports and occasionally writing down acquisitions that didn’t pan out. Novo’s deep pockets will go a long way to a turnaround, but only the future will tell if all these issues are fixed.

Kutay said his team is excited by the opportunity and was satisfied with the due diligence it did on the company.

“We believe we’re buying a strong company with a good management team and good prospects,” Kutay said. “If that wasn’t the case, I don’t think we’d be here.”

Amber Tong and Reynald Castañeda contributed reporting.

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Petrina Kamya, Ph.D., Head of AI Platforms at Insilico Medicine, presents at BIO CEO & Investor Conference

Petrina Kamya, PhD, Head of AI Platforms and President of Insilico Medicine Canada, will present at the BIO CEO & Investor Conference happening Feb….

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Petrina Kamya, PhD, Head of AI Platforms and President of Insilico Medicine Canada, will present at the BIO CEO & Investor Conference happening Feb. 26-27 at the New York Marriott Marquis in New York City. Dr. Kamya will speak as part of the panel “AI within Biopharma: Separating Value from Hype,” on Feb. 27, 1pm ET along with Michael Nally, CEO of Generate: Biomedicines and Liz Schwarzbach, PhD, CBO of BigHat Biosciences.

Credit: Insilico Medicine

Petrina Kamya, PhD, Head of AI Platforms and President of Insilico Medicine Canada, will present at the BIO CEO & Investor Conference happening Feb. 26-27 at the New York Marriott Marquis in New York City. Dr. Kamya will speak as part of the panel “AI within Biopharma: Separating Value from Hype,” on Feb. 27, 1pm ET along with Michael Nally, CEO of Generate: Biomedicines and Liz Schwarzbach, PhD, CBO of BigHat Biosciences.

The session will look at how the latest artificial intelligence (AI) tools – including generative AI and large language models – are currently being used to advance the discovery and design of new drugs, and which technologies are still in development. 

The BIO CEO & Investor Conference brings together over 1,000 attendees and more than 700 companies across industry and institutional investment to discuss the future investment landscape of biotechnology. Sessions focus on topics such as therapeutic advancements, market outlook, and policy priorities.

Insilico Medicine is a leading, clinical stage AI-driven drug discovery company that has raised over $400m in investments since it was founded in 2014. Dr. Kamya leads the development of the Company’s end-to-end generative AI platform, Pharma.AI from Insilico’s AI R&D Center in Montreal. Using modern machine learning techniques in the context of chemistry and biology, the platform has driven the discovery and design of 30+ new therapies, with five in clinical stages – for cancer, fibrosis, inflammatory bowel disease (IBD), and COVID-19. The Company’s lead drug, for the chronic, rare lung condition idiopathic pulmonary fibrosis, is the first AI-designed drug for an AI-discovered target to reach Phase II clinical trials with patients. Nine of the top 20 pharmaceutical companies have used Insilico’s AI platform to advance their programs, and the Company has a number of major strategic licensing deals around its AI-designed therapeutic assets, including with Sanofi, Exelixis and Menarini. 

 

About Insilico Medicine

Insilico Medicine, a global clinical stage biotechnology company powered by generative AI, is connecting biology, chemistry, and clinical trials analysis using next-generation AI systems. The company has developed AI platforms that utilize deep generative models, reinforcement learning, transformers, and other modern machine learning techniques for novel target discovery and the generation of novel molecular structures with desired properties. Insilico Medicine is developing breakthrough solutions to discover and develop innovative drugs for cancer, fibrosis, immunity, central nervous system diseases, infectious diseases, autoimmune diseases, and aging-related diseases. www.insilico.com 


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Another country is getting ready to launch a visa for digital nomads

Early reports are saying Japan will soon have a digital nomad visa for high-earning foreigners.

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Over the last decade, the explosion of remote work that came as a result of improved technology and the pandemic has allowed an increasing number of people to become digital nomads. 

When looked at more broadly as anyone not required to come into a fixed office but instead moves between different locations such as the home and the coffee shop, the latest estimate shows that there were more than 35 million such workers in the world by the end of 2023 while over half of those come from the United States.

Related: There is a new list of cities that are best for digital nomads

While remote work has also allowed many to move to cheaper places and travel around the world while still bringing in income, working outside of one's home country requires either dual citizenship or work authorization — the global shift toward remote work has pushed many countries to launch specific digital nomad visas to boost their economies and bring in new residents.

Japan is a very popular destination for U.S. tourists. 

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This popular vacation destination will soon have a nomad visa

Spain, Portugal, Indonesia, Malaysia, Costa Rica, Brazil, Latvia and Malta are some of the countries currently offering specific visas for foreigners who want to live there while bringing in income from abroad.

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With the exception of a few, Asian countries generally have stricter immigration laws and were much slower to launch these types of visas that some of the countries with weaker economies had as far back as 2015. As first reported by the Japan Times, the country's Immigration Services Agency ended up making the leap toward a visa for those who can earn more than ¥10 million ($68,300 USD) with income from another country.

The Japanese government has not yet worked out the specifics of how long the visa will be valid for or how much it will cost — public comment on the proposal is being accepted throughout next week. 

That said, early reports say the visa will be shorter than the typical digital nomad option that allows foreigners to live in a country for several years. The visa will reportedly be valid for six months or slightly longer but still no more than a year — along with the ability to work, this allows some to stay beyond the 90-day tourist period typically afforded to those from countries with visa-free agreements.

'Not be given a residence card of residence certificate'

While one will be able to reapply for the visa after the time runs out, this can only be done by exiting the country and being away for six months before coming back again — becoming a permanent resident on the pathway to citizenship is an entirely different process with much more strict requirements.

"Those living in Japan with the digital nomad visa will not be given a residence card or a residence certificate, which provide access to certain government benefits," reports the news outlet. "The visa cannot be renewed and must be reapplied for, with this only possible six months after leaving the countr

The visa will reportedly start in March and also allow holders to bring their spouses and families with them. To start using the visa, holders will also need to purchase private health insurance from their home country while taxes on any money one earns will also need to be paid through one's home country.

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