Connect with us

News

Alzheimer’s drug Leqembi backed by FDA expert panel for full approval

Published

on

Breakthrough Alzheimer’s drug Leqembi has received the unanimous support of a US Food and Drug Administration advisory panel – all but ensuring full approval for the first of its class treatment.

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) voted 6-0 that data showed Leqembi – also known as lecanemab – demonstrated a clinical benefit to patients.

The PCNS came to its decision after reviewing evidence from a Phase 3 Clarity AD clinical trial that showed Leqembi slowed cognitive and functional decline in patients by 27% compared to a placebo at 18 months.

The FDA will decide on July 6 whether to endorse the drug made by Japanese pharmaceutical company Eisai and Massachusetts-based global biotechnology firm Biogen.

Leqembi received accelerated approval from the FDA for the treatment of early Alzheimer’s disease on January 6, 2023 and was launched in the US on January 18 this year.

The accelerated approval which allows for faster consent for drugs for serious conditions that fill an unmet medical need, was based on Phase 2b data that demonstrated that Leqembi reduced the accumulation of amyloid-beta plaque in the brain, a neuropathological hallmark of Alzheimer’s disease.

But this approval restricted Leqembi, which is administered twice a month intravenously, to patients who could either pay $26,500 a year or, in the case of the US Government’s Medicare national health insurance programme for seniors and the disabled, to those who were enrolled on a clinical trial. This even though there are no clinical trials underway.

However, FDA approval would mean that Leqembi would become more readily available through Medicare with the agencies running the programme, The Centers for Medicare and Medicaid Services (CMS), having promised to broadly cover the cost of the drug for patients who are willing to take part in a national data registry to track “evidence about how these drugs work in the real world.”

But that listing has yet to be created and the US-based Alzheimer’s Association has described making registry a condition of coverage an “unnecessary and potentially harmful barrier.”

Joanne Pike, the Alzheimer’s Association’s president and CEO, said: “We are in full agreement with the FDA Advisory Committee that Leqembi provides clinical benefit and that this benefit outweighs the risks.

“Now all eyes turn to CMS. Medicare is supposed to be a rock-solid guarantee for Americans, and it is time for CMS to step up and provide Medicare access on the day of an FDA traditional approval.

Alzheimer’s drug Leqembi. Image: Eisai Co.

“Americans living with Alzheimer’s disease deserve access to FDA-approved therapies without barriers, just like people with cancer, heart disease and HIV/AIDS.”

According to the Alzheimer’s Association, 6.5 million Americans are currently living with the disease, which robs patients of their memory and causes other cognitive problems.

The organisation says Alzheimer’s and other dementias will cost the US $345bn this year. That cost is predicted to rise to $11bn annually by 2050 as more people are diagnosed with the condition.

Leqembi, which is an anti-amyloid treatment, changes the course of Alzheimer’s and has been shown to deliver clear clinical benefit for people in the early stages of the disease.

By slowing progression in the early stages of Alzheimer’s, the treatment will give people more time to participate fully in daily life, help make important decisions, and live independently.

This could mean more time for a person to take care of family finances, and engage in hobbies and interests.

Phase 3 data from the Clarity AD global clinical trial published in the New England Journal of Medicine showed Leqembi met both the primary and all key secondary endpoints for the patient population with highly statistically significant results.

As with other anti-amyloid treatments in this class of drugs, Leqembi does have side effects, including brain swelling and bleeding.

Three deaths from brain haemorrhages occurred in the extended part of the trial. The FDA said the patients had a disorder called cerebral amyloid angiopathy, which is the build up of amyloid in small arteries and capillaries in the brain, a condition that can be difficult to detect by imaging tests.

Despite this, Dr Pike has welcomed the FDA Advisory Committee’s decision. She said: “The Alzheimer’s Association welcomes and celebrates this action by the FDA Advisory Committee to support traditional approval of Leqembi for people with early Alzheimer’s.

“With this action we are one step closer to more people living with Alzheimer’s having more time with more of their capabilities intact – to do the things they want to do and love to do best.”

Myra Garcia, a member of the Alzheimer’s Association Early Stage Advisory Group, spoke to the committee hearing and said: “While the thought of a cure for Alzheimer’s disease is certainly part of my optimism, I’d like you to know that for me, more time is enough for now. And that is the promise of treatments like lecanemab.”

News

Gut microbes from aged mice induce inflammation in young mice

Published

on

Findings from a new study suggest that changes to the gut microbiome play a role in the systemwide inflammation that often occurs with ageing.

When scientists transplanted the gut microbes of aged mice into young “germ-free” mice — raised to have no gut microbes of their own — the recipient mice experienced an increase in inflammation that parallels inflammatory processes associated with ageing in humans. Young germ-free mice transplanted with microbes from other young mice had no such increase.

Published in Aging Cell, the study also found that antibiotics caused longer-lasting disruptions in the gut microbiomes of aged mice than in young mice.

“There’s been a growing consensus that ageing is associated with a progressive increase in chronic low-grade inflammation,” said Jacob Allen, a professor of kinesiology and community health at the University of Illinois Urbana-Champaign who led the new research with Thomas Buford, a professor of medicine at the University of Alabama at Birmingham.

“And there’s a kind of debate as to what drives this, what is the major cause of the ageing-induced inflammatory state. We wanted to understand if the functional capacity of the microbiome was changing in a way that might contribute to some of the inflammation that we see with ageing.”

Previous studies have found associations between age-related changes in the microbial composition of the gut and chronic inflammatory diseases such as Parkinson’s disease and Alzheimer’s disease. Some studies have linked microbial metabolism to an individual’s susceptibility to other health conditions, including obesity, irritable bowel syndrome and heart disease. Age-related changes in the gut microbiome also may contribute to the so-called leaky gut problem, the researchers said.

“Microbiome patterns in aged mice are strongly associated with signs of bacterial-induced barrier disruption and immune infiltration,” they wrote.

“The things that are in our gut are supposed to be kept separate from the rest of our system,” Buford said. “If they leak out, our immune system is going to recognize them. And so then the question was: ‘Is that a source of inflammation?’”

Many studies have compared the relative abundance and diversity of species of microbes in the gut, offering insight into some of the major groups that contribute to health or disease. But sequencing even a portion of the microbes in the gut is expensive and the results can be difficult to interpret, Allen said. That is why he and his colleagues focused on microbial function — specifically, how the gut microbiomes of ageing mice might spur an immune response.

The team focused on toll-like receptors, molecules that mediate inflammatory processes throughout the body. TLRs sit in cellular membranes and sample the extracellular environment for signs of tissue damage or infection. If a TLR encounters a molecule associated with a potential pathogen — for example, a lipopolysaccharide component of a gram-negative bacterium — it activates an innate immune response, calling in pro-inflammatory agents and other molecules to fight the infection.

The researchers first evaluated whether the colonic contents of young and aged mice were likely to promote TLR signalling. They found that microbes from aged mice were more likely than those from young mice to activate TLR4, which can sense lipopolysaccharide components of bacterial cell walls. A different receptor, TLR5, was not affected differently in aged or young mice. TLR5 senses a different bacterial component, known as flagellin.

Young germ-free mice transplanted with the microbes of aged mice also experienced higher inflammatory signalling and increased levels of lipopolysaccharides in the blood after the transplants, the team found.

This finding provides “a direct link between ageing-induced shifts in microbiota immunogenicity and host inflammation,” the researchers wrote.

In other experiments, the team treated mice with broad-spectrum antibiotics and tracked changes in the microbiomes during treatment and for seven days afterward.

“One of the most interesting questions for me was what microbes come back immediately after the treatment with antibiotics ends,” Buford said. And in the mice with aged microbiota in their guts, “these opportunistic pathogens were the most quick to come back.”

“It appears that as we age our microbiome might be less resilient to antibiotic challenges,” Allen said. “This is important because we know that in the U.S. and other Western societies, we’re increasingly exposed to more antibiotics as we age.”

The study is an important step toward understanding how age-related microbial changes in the gut may affect long-term health and inflammation, the researchers said.

Co-authors of the study also included Illinois postdoctoral researcher Elisa Caetano-Silva; U. of I. Ph.D. student Akriti Shrestha; National Children’s Hospital research scientist Michael Bailey; and Jeffrey Woods, the director of the Center on Health, Aging and Disability at Illinois.

Allen also is a professor of nutritional sciences at Illinois and an affiliate of the Carl R. Woese Institute for Genomic Biology at the U. of I.

Continue Reading

News

Evening exercise benefits elderly hypertensives

Published

on

Evening exercise benefits elderly hypertensives

A study conducted at the University of São Paulo with 23 volunteers found that aerobic exercise performed in the evening benefits elderly hypertensives more than morning exercise.

Aerobic training is known to regulate blood pressure more effectively when practiced in the evening than in the morning.

Researchers who conducted a study of elderly patients at the University of São Paulo’s School of Physical Education and Sports (EEFE-USP) in Brazil concluded that evening exercise is better for blood pressure regulation thanks to improved cardiovascular control by the autonomic nervous system via a mechanism known as baroreflex sensitivity.

Leandro Campos de Brito, first author of the article, commented: “There are multiple mechanisms to regulate blood pressure, and although morning training was beneficial, only evening training improved short-term control of blood pressure by enhancing baroreflex sensitivity.

“This is important because baroreflex control has a positive effect on blood pressure regulation, and there aren’t any medications to modulate the mechanism.”

In the study, 23 elderly patients diagnosed and treated for hypertension were randomly allocated into two groups: morning training and evening training. Both groups trained for ten weeks on a stationary bicycle at moderate intensity, with three 45-minute sessions per week.

Key cardiovascular parameters were analysed, such as systolic and diastolic blood pressure, and heart rate after ten minutes’ rest. The data was collected before and at least three days after the volunteers completed the ten weeks of training.

The researchers also monitored mechanisms pertaining to the autonomic nervous system, which controls breathing, heart rate, blood pressure, digestion, and other involuntary bodily functions, such as muscle sympathetic nerve activity, which regulates peripheral blood flow via contraction and relaxation of blood vessels in muscle tissue, and sympathetic baroreflex sensitivity, assessing control of blood pressure via alterations to muscle sympathetic nerve activity.

In the evening training group, all four parameters analysed were found to improve: systolic and diastolic blood pressure, sympathetic baroreflex sensitivity, and muscle sympathetic nerve activity. In the morning training group, no improvements were detected in muscle sympathetic nerve activity, systolic blood pressure or sympathetic baroreflex sensitivity.

“Evening training was more effective in terms of improving cardiovascular autonomic regulation and lowering blood pressure. This can be partly explained as due to an improvement in baroreflex sensitivity and a reduction of muscle sympathetic nerve activity, which increased in the evening. For now, all we know is that baroreflex control is the decisive factor, from the cardiovascular standpoint at least, to make evening training more beneficial than morning training, since it induces the other benefits analysed. However, much remains to be done in this regard in order to obtain a better understanding of the mechanisms involved,” said Brito, who is currently a professor at Oregon Health & Science University’s Oregon Institute of Occupational Health Sciences in the United States, and continues to investigate the topic via circadian rhythm studies.

Baroreflex sensitivity regulates each heartbeat interval and controls autonomic activity throughout the organism.

“It’s a mechanism that involves sensitive fibres and deformations in the walls of arteries in specific places, such as the aortic arch and carotid body. When blood pressure falls, this region warns the brain region that controls the autonomic nervous system, which in turn signals the heart to beat faster and tells the arteries to contract more strongly. If blood pressure rises, it warns the heart to beat more slowly and tells the arteries to contract less. In other words, it modulates arterial pressure beat by beat,” Brito explained.

In previous studies, the EEFE-USP research group showed that evening aerobic training reduced blood pressure more effectively than morning training in hypertensive men (read more at: agencia.fapesp.br/34194), and that the more effective response to evening training in terms of blood pressure control was accompanied by a greater reduction in systemic vascular resistance and systolic pressure variability (read more at: agencia.fapesp.br/37432).

“Replication of the results obtained in previous studies and in different groups of hypertensive patients, associated with the use of more precise techniques to evaluate the main outcomes, has strengthened our conclusion that aerobic exercise performed in the evening is more beneficial to the autonomic nervous system in patients with hypertension. This can be especially important for those with resistance to treatment with medication,” Brito said.

Continue Reading

News

Revolutionising cancer treatment: intracellular protein delivery using hybrid nanotubes

Published

on

Revolutionising cancer treatment: intracellular protein delivery using hybrid nanotubes

A new hybrid nanotube stamp system has been developed which revolutionises precision medicine with high efficiency and cell viability rates for cancer treatment.

Precision medicine and targeted therapies are gaining traction for their ability to tailor treatments to individual patients while minimising adverse effects. Conventional methods, such as gene transfer techniques, show promise in delivering therapeutic genes directly to cells to address various diseases.

However, these methods face significant drawbacks, hindering their efficacy and safety. Intracellular protein delivery offers a promising approach for developing safer, more targeted, and effective therapies. By directly transferring proteins into target cells, this method circumvents issues such as silencing during transcription and translation and the risk of undesirable mutations from DNA insertion. Additionally, intracellular protein delivery allows for precise distribution of therapeutic proteins within target cells without causing toxicity.

A group of researchers led by Professor Takeo Miyake at Waseda University, Japan in collaboration with the Mikawa Group at the RIKEN Institute have now developed a hybrid nanotube stamp system for intracellular delivery of proteins. This innovative technique enables the simultaneous delivery of diverse cargoes, including calcein dye, lactate oxidase (LOx) enzyme, and ubiquitin (UQ) protein, directly into adhesive cells for cancer treatment.

The researchers explored the therapeutic potential of delivering LOx enzyme for cancer treatment. “Through our innovative stamp system, we successfully delivered LOx into both healthy mesenchymal stem cells (MSC) and cancerous HeLa cells. While MSC cells remained unaffected, we observed significant cell death in HeLa cancer cells following LOx treatment with viabilities decreasing over time. Our findings highlight the promising efficacy of intracellularly delivered LOx in selectively targeting and killing cancer cells, while sparing healthy cells, offering a targeted therapeutic strategy for cancer treatment,” explains Miyake.

Finally, the team successfully delivered 15N isotope-labeled UQ proteins into HeLa cells using the HyNT stamp system. This delivery allowed for the analysis of complex protein structures and interactions within the cells. In addition, optical and fluorescence imaging confirmed the presence of delivered UQ in HeLa cells, and nuclear magnetic resonance spectroscopy matched the intracellular UQ protein concentration with that of a solution containing 15N-labeled UQ. These results demonstrate the effectiveness of the stamp system in delivering target proteins for subsequent analysis.

The results demonstrate the remarkable capability of the HyNT stamp system in delivering LOx and UQ into a substantial number of adhesive cells, as required for regenerative medicine applications. The system achieved a notably high delivery efficiency of 89.9%, indicating its effectiveness in transporting therapeutic proteins into the target cells with precision. Moreover, the cell viability rate of 97.1% highlights the system’s ability to maintain the health and integrity of the treated cells throughout the delivery process.

The HyNT stamp system offers transformative potential in intracellular protein delivery, with applications spanning from cancer treatment to molecular analysis. Beyond medicine, its versatility extends to agriculture and food industries, promising advancements in crop production and food product development. With precise cell manipulation and efficient delivery, the HyNT stamp system is poised to revolutionize biomedical research, clinical practice, and diverse industries, paving the way for personalized interventions and shaping the future of modern medicine.

Continue Reading

Trending