Publisher Health

The drug is safe, and one trial found it may extend survival and slow paralysis in functions like muscle control and speaking. A larger trial will be completed in 2024.The Food and Drug Administration on Thursday approved an experimental treatment for A.L.S., a severe neurological disorder that causes paralysis and death, despite questions about the therapy’s effectiveness.The treatment, conceived about a decade ago by two college students, was approved even though analyses by the F.D.A.’s reviewers concluded there was not yet sufficient evidence that the medication could help patients live longer or slow the rate at which they lose functions like muscle control, speaking or breathing without assistance. Nevertheless, the agency decided to greenlight the drug without waiting two years for results of a large clinical trial, citing data showing the treatment to be safe and the desperation of patients with a disease that often causes death within two-to-five years.The drug, which has the scientific name AMX0035, will be marketed as Relyvrio. In a summary memorandum about the drug the F.D.A. wrote that there was “residual uncertainty about the evidence of effectiveness,” but that “given the serious and life-threatening nature of A.L.S. and the substantial unmet need, this level of uncertainty is acceptable in this instance.” The memorandum also said that the benefits outweigh the risks because the treatment is “without any significant safety signals of concern.”The approval follows an impassioned campaign by patients and advocacy groups. In addition, doctors who treat A.L.S. patients had urged approval in a letter to the F.D.A. and testimony and in testimony before an F.D.A. advisory committee.“In your difficult job, there’s always going to be a chance of making a mistake; it comes down to which mistake you would rather make,” Dr. Richard Bedlack, director of the A.L.S. clinic at Duke University, testified this month. “To approve AMX0035 and find out in two years that it doesn’t work — I doubt many are going to be very angry because people with A.L.S. got to try something that was safe and appeared promising in 2022.”But, he added, “Can you imagine the mistake of saying no and then getting confirmatory evidence in two years that this really did work? And realizing all those patients were much more disabled or even dead when they didn’t need to be? I don’t know how you’ll be able to live with yourself if you make that mistake.”A.L.S., or amyotrophic lateral sclerosis, also called Lou Gehrig’s disease, is diagnosed in about 6,000 people worldwide each year. There are only two other approved A.L.S. medications in the United States: riluzole, approved in 1995, which can extend survival by several months, and edaravone, approved in 2017, which can slow progression by about 33 percent.The Fight Against A.L.S.The illness, also called Lou Gehrig’s disease, robs people of their ability to move, speak, eat and ultimately breathe.Relyvrio: The experimental treatment for A.L.S. conceived a decade ago by two college students received the Food and Drug Administration’s approval, despite questions about its effectiveness.A Runner’s Mission: After surpassing the average life expectancy for people with the disease, Andrea Peet decided to race a new kind of clock: 50 marathons in 50 states.Brain Implant: A man who is fully paralyzed by A.L.S. was able to communicate using only his thoughts.Rethinking Care: In 2017, Brian Wallach was diagnosed with A.L.S. Now, his startup aims to help other patients make the most of their time.Relyvrio was conceived by Justin Klee and Joshua Cohen when they were undergraduate students at Brown University. They proposed that combining taurursodiol, a supplement sometimes used to regulate liver enzymes, and sodium phenylbutyrate, a medication for a pediatric urea disorder, could protect neurons in the brain from damage in diseases like A.L.S. by preventing dysfunction of two structures in cells: mitochondria and the endoplasmic reticulum. They later founded a small Massachusetts company, Amylyx Pharmaceuticals.As patients learned about the compound, some began obtaining the ingredients on their own from Amazon and other sources. In June, Canada became the first country to approve the treatment, under a special condition requiring Amylyx to later provide better evidence that it worked. Advocacy groups predicted that some American patients would seek it from Canada, where it is marketed as Albrioza, if the F.D.A. didn’t approve it.The two-drug combination was conceived by Justin Klee, left, and Joshua Cohen when they were undergraduates at Brown University.Cody O’Loughlin for The New York TimesAmylyx did not immediately say what price it is considering for the treatment in the United States and has said the price is still being negotiated in Canada.  “Amylyx’s goal is that every person who is eligible for Relyvrio will have access as quickly and efficiently as possible as we know people with A.L.S. and their families have no time to wait,” the company said in a statement after the F.D.A. announcement.The medication, a bitter-tasting powder mixed with water and either drunk or ingested through a feeding tube, traveled an unusual and controversial path to approval. The F.D.A. typically requires two persuasive clinical trials, usually Phase 3 trials, which are larger and more extensive than Phase 2 studies. For serious diseases with few treatments, the agency can accept one trial plus additional confirmatory data.For Relyvrio, the data comes only from one Phase 2 trial in which 137 patients took either the drug or a placebo, plus an extension study that followed some patients after the trial ended when they were knowingly taking the drug.The Phase 2 trial involved patients considered to have fast-progressing disease. Two-thirds of participants received Relyvrio. Over 24 weeks, they experienced a 25 percent slower decline than participants receiving placebo — declining 2.32 points less on a 48-point A.L.S. scale that rates 12 physical abilities, including walking, speaking, swallowing, dressing, handwriting and breathing.The open-label extension study involved 90 of those patients, including 34 from the placebo group, who began taking the medication about seven months after those who received it from the beginning. Patients who received the treatment the longest had a median of about 6.5 months more time before being hospitalized, being put on a ventilator or dying, Amylyx reported. Researchers later published another analysis that suggested additional benefit.The F.D.A. initially recommended that Amylyx not apply for approval until the Phase 3 trial was completed in 2024.A.L.S. advocacy groups campaigned vehemently to persuade the F.D.A. to reconsider, especially after the agency’s controversial approval last year of the Alzheimer’s drug Aduhelm despite doubts about whether it worked. Soon after, F.D.A. officials began suggesting that Amylyx submit an application for approval using existing data.In March, a committee of independent advisers to the F.D.A. voted by a narrow margin that the treatment had not yet been shown to be effective, a conclusion also reached by the F.D.A.’s own reviewers. The agency then allowed Amylyx to submit more data and took the unusual step of scheduling a second independent advisory committee meeting on Sept. 7. In a report presented there, agency reviewers said they also considered the new data insufficient.But Dr. Billy Dunn, director of the F.D.A.’s office of neuroscience, told the advisory committee that “although some might reasonably argue that substantial evidence does not currently exist” to justify approval, the agency should exercise “the broadest flexibility” by also considering the seriousness of the disease and the dearth of available treatments.Dr. Dunn posed a question to the company: If the treatment received approval now and was shown to be ineffective in the Phase 3 trial, would Amylyx voluntarily withdraw it from the market, saving the agency a lengthy recall process? Mr. Klee said the company would.That commitment by Amylyx, plus emotional testimony from patients and doctors, persuaded more advisory committee members at the September meeting, where the vote favoring approval was seven to two.One of those who voted against approval, Dr. Kenneth Fischbeck, a distinguished investigator for the National Institutes of Health, said the company could provide the therapy to patients for free while waiting for better evidence, but “I don’t think it’s met the standard of evidence to allow them to sell the drug.” Mark Weston, a member of the advisory committee who has A.L.S., said he was disappointed that the new information the company presented wasn’t stronger. “I was hoping for something more,” he said. But Mr. Weston, who earlier in the meeting named A.L.S. patients who had died since the March hearing, said he voted for approval because “I can’t decouple my thoughts about that from my thoughts about the unmet need.”That need for treatments was the overwhelming message of patients who testified. “Instead of thinking you are protecting me I want you to recommend approval so that I have the chance to live,” said Brian Wallach, 41, who co-founded “I AM ALS,” an advocacy group, in testimony mostly read by a friend because A.L.S. has profoundly damaged his ability to speak.Gregory Canter, one of the clinical trial participants, said “the rate of my functional decline has slowed considerably” since beginning the drug over three years ago.“A.L.S. is the basement; this starts us up the stairs,” Mr. Canter said. “It won’t get us to the top alone, but each step up is important to point us in the right direction.”Calaneet Balas, president and chief executive of the A.L.S. Association, said in a statement that the F.D.A. decision was “a victory for the entire ALS community, which came together to advocate for early approval of AMX0035.” The association and other advocacy groups met with F.D.A. officials, submitted a petition with over 50,000 signatures and organized a campaign generating over 13,000 emails to the agency.The A.L.S. Association contributed $2.2 million to the development and study of AMX0035, using money raised through the 2014 Ice Bucket Challenge. Amylyx agreed to use sales of the drug to repay 150 percent of the association’s grant to fund more research.

Non-invasive sensors laid on the skin’s surface to measure bioelectrical activity could offer a better alternative for patients suffering with poor gut health.
Stefan Calder, a recent PhD graduate at the Auckland Bioengineering Institute (ABI), at Waipapa Taumata Rau, University of Auckland is the lead and joint-first author for two papers published in scientific journals this month on gut health. Stefan says gastric disorders are increasingly prevalent in humans, but reliable non-invasive tools to objectively assess gastric function are lacking.
“Many people suffering with chronic gut issues are on a constant diagnostic treadmill of antibiotics or proton pump inhibitors until they are sent for an endoscopy. A reliable surface-based recording could bridge the gap between symptom-based diagnostics and the more invasive minor surgery tests.”
Like the rhythmic beatings of the heart, gut movements depend on bioelectrical activity — but the electrical activity in the gut has been much more difficult to reliably detect. Researchers at ABI and the Faculty of Medical and Health Sciences’ Department of Surgery have employed a novel device using a sticky patch of sensors and a recording device and associated techniques to create a new and reliable non-invasive tool to map electrical waves from the stomach.
Coined “Body Surface Gastric Mapping” (BSGM), the method has proven a reliable detector of gastric slow wave activity and has now led to an exciting and unexpected discovery identifying two distinct disease subgroups in chronic nausea and vomiting syndromes.
The first paper published in The American Journal of Physiology-Gastrointestinal and Liver Physiology, explored the use of the mapping tool in pigs as a pre-clinical study to validate the BSGM prior to advancing to clinical trials in human patients. BSGM has shown to reliably record bio-electrical activity on the gut’s surface and accurately detect changes in both the frequency or rhythm, and direction of electromagnetic waves with intricate detail.
The second paper published in Science Translational Medicine set out to explore the degree of difference in bio-electrical activity between healthy people and patients with chronic nausea and vomiting syndromes defined by the novel gastric mapping device. While previous surgical and non-invasive studies have shown that gastric dysfunctions are associated with abnormal bio-electrical slow waves, the researchers found surprising results.
“Approximately two-thirds of the symptomatic patient group had completely normal bio-electrical activity, while the rest had abnormal activity. We realised there were two sub types of what was previously considered a single disease.
“This may go on to explain or further classify that single disease into two diseases based on different mechanisms. For example, abnormal bioelectrical activity is likely to point to something intrinsically wrong with the stomach itself, but for those patients who show a completely normal slow wave propagation, their issue is likely arising from somewhere else.
“This idea of recording electrical activity on the body’s surface has been around for a long time. ECG machines, recording electrical activity have gained diagnostic acceptance for the last 100 years, but in the gut that is not the case. Through these studies we have validated a device and process that can reliably and accurately evidence bioelectrical activity in the stomach. We also show that bioactivity in the stomach can be a useful biological marker for disease.
“With this bio-electrical information on hand to inform clinical guidance or treatment, people experiencing chronic vomiting or nausea may be directed to different pathways and may receive diagnosis and more appropriate treatment options sooner.”
Story Source:
Materials provided by University of Auckland. Note: Content may be edited for style and length.

Severe brain injury that develops slowly after preterm births, causing the likes of cerebral palsy, may be treatable, new research from the University of Auckland finds.
Over a third of cases of cerebral palsy are still linked to being born extremely prematurely. Clinical studies have shown that severe injury can appear many weeks after birth. “The current thinking is that this form of brain injury is so severe that there is no point trying to understand it, let alone treat it,” says senior research fellow Dr Christopher Lear, lead author on the new study. “Just the concept that it might be treatable is revolutionary.”
The University of Auckland team showed, in an animal model, that there was intense local inflammation before the injury developed.
Critically, giving the well-established anti-inflammatory drug, Etanercept (also known as ‘Enbrel’) three days after a period of oxygen deprivation was able to almost completely prevent severe injury from developing after three weeks’ recovery. The article has just been published in a leading journal, Brain. “Virtually all proposed treatments so far need to be started within the first six hours of life,” says Professor Laura Bennet. “This is often not realistic when families are overwhelmed by events around birth.”
“A therapeutic window of at least three days is exceptionally long. Much more research is needed before this approach can be tested in humans, but this remarkably wide window for treatment gives us real hope that these findings will one day lead to a new treatment in humans to prevent cerebral palsy,” says Professor Bennet.
The team are from the Fetal Physiology and Neuroscience Group in the Department of Physiology.
This research was supported by a 2017 programme grant of $4,919,534 from the Health Research Council of New Zealand (HRC).
Story Source:
Materials provided by University of Auckland. Note: Content may be edited for style and length.

While illegal for recreational use, psychedelic drugs are showing great promise as treatments for severe depression and anxiety, as well as alcohol addiction and other conditions. Some advocates and scientists believe the actual psychedelic trip — hallucinations and profound emotional experiences- is what leads to long-lasting therapeutic effects. Other scientists speculate that if the ‘trip’ could be eliminated from such drugs, then only the therapeutic effects might remain. Researchers at UNC-Chapel Hill, UC San Francisco, Yale, Duke, and Stanford have taken a major step toward answering that question.
Published in Nature, this research in animal models show it’s possible to create a compound that hits the same exact target as psychedelic drugs hit — the 5-HT2A serotonin receptors on the surface of specific neurons — but does not cause the same psychedelic effects when given to mice. The new compound triggers the same anti-depressant action that researchers have long observed in mice treated with SSRI drugs over the past two decades, with just two differences: the anti-depressant action of the new compound was immediate and long-lasting after just one dose.
“We were very surprised the compound had any anti-depressant activity similar to ketamine and psilocybin, both rapidly acting antidepressant psychedelic drugs,” said co-senior author Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology at the UNC School of Medicine and director of the NIMH Psychoactive Drug Screening Program. “We were basically running a chemistry experiment to see if we could create a compound to activate 5-HT2A. Once we achieved that, we decided to run experiments in mice.”
The compound is patented by Yale, UNC-Chapel Hill, and UCSF and licensed to Onsero, a company created to fine-tune experimental compounds before they can be further tested in clinical trials.
“We don’t know if we’ll see the same effects in people,” Roth said. “But we hope to find out. It would be a game changer to create a one-dose, long-acting therapy to help people with treatment-resistant depression and other conditions.”
The Case for Psychedelics
When someone eats a magic mushroom, the active ingredient pscilocin — which is derived from psilocybin — binds tightly to the 5-HT2A serotonin receptors on the surface of neurons. The receptor is activated for a long time, triggering a cascade of chemical signals inside cells. These cells then communicate to other cells throughout the brain, sending the person on a long, strange hallucinogenic trip for hours. For those who are treatment-resistant, psychedelic drugs can immediately alleviate depression, and the effect lasts for many months.

Every living cell relies on proteins in order to function and the process of protein synthesis — translation — is critical for survival. Bacteria are no exception, with molecular machines involved in translation being one of the most common targets for antibiotics.
Now, for the first time, scientists led by Julia Mahamid’s group at EMBL Heidelberg have visualised at atomic detail how antibiotics affect the process of protein production inside bacterial cells. This study, published in Nature, also marks the first time when scientists have observed atomic-level structural changes in the active translation machinery directly inside a cell, rather than using isolated molecules in a test tube. Importantly, this approach allowed them to identify mechanisms that such machines use to “talk” to each other inside cells.
The study was carried out in collaboration with researchers from the Max-Planck-Institute for Biophysical Chemistry, Göttingen, the Wellcome Centre for Cell Biology, University of Edinburgh, and Technische Universität Berlin. The research also involved contributions from the Zimmermann-Kogadeeva and Bork groups at EMBL Heidelberg, who helped the researchers carry out bioinformatics analyses to observe what diversity in ribosomal proteins looks like across >4000 representative bacteria.
Minuscule bacteria and molecular machines
Mahamid and her team are experts in studying the bacterium Mycoplasma pneumoniae using a technique called cryo-electron tomography (cryo-ET). This tiny bacterium, which causes atypical pneumonia in humans, has a fully-functional protein synthesis machinery, despite being only about ten-thousandth of a millimetre in size.
“We chose Mycoplasma for our studies because they are among the smallest and most minimal living cells, and have been widely used as model cells in systems biology and synthetic biology studies,” said Liang Xue, postdoc in the Mahamid group and the first author of the study.

The number of Americans with cardiovascular disease who are food insecure — having limited or uncertain access to adequate food — has skyrocketed over the last 20 years, a national study finds.
A Michigan Medicine team analyzed data from the National Health and Nutrition Examination Survey representing 312 million American adults between 1999 and 2018, finding that 38% of people with cardiovascular disease were food insecure in 2017-2018. That number has more than doubled from two decades earlier, when the rate of food insecurity was 16.3%. The findings are published in JAMA Cardiology.
“Food insecurity is a common problem among people with cardiovascular disease, and we are seeing that issue become even more prevalent in recent years,” said Eric J. Brandt, M.D., M.H.S., FACC, lead author of the study and a cardiologist at the University of Michigan Health Frankel Cardiovascular Center.
“We believe there is a two-way relationship here. Individuals who are food insecure may have increased risk for cardiovascular disease, and vice versa. When one acquires heart disease, it impacts one’s risk for developing socioeconomic problems that could reduce access to adequate and quality food. Food insecurity can often occur with other social determinants of health, such as poor transportation access or access to healthcare, which further compounds this relationship.”
In the overall population, Black and Hispanic adults were more likely to report food insecurity. Since 2011, 24% of Hispanic adults and 18% of Black adults were food insecure, compared to 8% of Asian adults and 13% of white adults.
Researchers conclude that cardiovascular disease is associated with a higher risk for food insecurity. Those adults were more than two times likely to be food insecure than those without the cardiovascular disease.
“Food insecurity has the potential to exacerbate existing racial and ethnic health disparities,” Brandt said. “But there is also a public realization here that differences in cardiovascular outcomes across races and ethnicities aren’t related to the racial or ethnic origin of an individual, rather more to the social experience of an individual. In this broader viewpoint, having had a cardiovascular event could have a major impact on one’s social circumstance that places them at risk for food insecurity and other socioeconomic difficulties.”
Cardiovascular disease remains the leading cause of death in the United States, and diet is the greatest contributor to death from such disease — accounting for over 400,000 deaths in 2016, according to The US Burden of Disease Collaborators.
Those experiencing food insecurity are more likely to shoulder a greater burden from diet-related cardiovascular disease. They are also more likely to be stressed and not take prescription medication to treat cardiometabolic risk factors, such as diabetes and high blood pressure.
As food insecurity remains a potent social determinant of health, researchers say it’s important for clinicians and health systems to use validated screening techniques to detect food insecurity among patients.
“Healthcare providers can impact the health and overall wellbeing of their patients by addressing food insecurity,” said co-author Tammy Chang, M.D., M.P.H., M.S., family physician at U-M Health and co-director of the National Clinician Scholars Program at the U-M Institute for Healthcare Policy and Innovation.
“More patients than you may think are impacted by food insecurity. A team-based approach including social workers, case managers and social service departments can help patients get connected with local resources. If we are serious about promoting health, healthcare providers need to ensure people have access to healthy foods and don’t go hungry.”
Story Source:
Materials provided by Michigan Medicine – University of Michigan. Original written by Noah Fromson. Note: Content may be edited for style and length.

People with high blood pressure levels face a faster erosion of their ability to think, make decisions and remember information than those with normal blood pressure levels, a new study finds.
The researchers traced high blood pressure’s association with declining brain function over years, in data from six large studies that they pooled and analyzed. They show that blood pressure-related cognitive decline happens at the same pace in people of Hispanic heritage as in non-Hispanic white people.
The team had set out to see if differences in long-term blood pressure control explained why Hispanic people face a 50% higher overall risk of dementia by the end of their life than non-Hispanic white people in the United States.
But the new findings suggest that other factors may play a bigger role in that disparity.
Nevertheless, the new study in the Journal of Alzheimer’s Disease serves as an important reminder of the key role that controlling blood pressure plays in long-term brain health, says Deborah Levine, M.D., M.P.H., lead author of the study and director of the University of Michigan’s Cognitive Health Services Research Program.
“Our findings suggest that high blood pressure causes faster cognitive decline, and that taking hypertension medication slows the pace of that decline,” says Levine, a professor of internal medicine at the U-M’s academic medical center, Michigan Medicine.

Like bacteria, yeasts are found everywhere, even in and around our bodies. And, as with bacteria, you can become infected by yeasts and become ill. Yeasts infect about 150 million people a year and kill about 1.7 million, especially those who are immunocompromised.
Yeast cells and human immune system cells rely on surprisingly similar chemical reactions to know when to grow. University of Arizona scientists have identified subtle differences between the two cell types that could help spur the development of antifungal drugs that are able to attack disease-causing yeasts in the body while sparing the immune system.
Their findings, published in the journal eLife, not only have implications for drug development, they also provide important insight into the evolution of an ancient growth control pathway found in all multicellular organisms.
It is well known in the scientific community that a conglomerate of proteins called TORC1 — short for Target of Rapamycin kinase Complex 1 — controls the growth of cells in everything from humans to yeasts. But researchers have now identified and named the protein that triggers this process in yeasts — a nutrient sensor and TORC1 regulator they named Ait1. When working normally, Ait1 shuts down TORC1 in yeasts when cells are starved for nutrients, blocking cell growth.
“Ait1 is kind oflike a hand holding TORC1 in place, with a finger that reaches over the top and flicks TORC1 on and off depending on how many nutrients a cell has,” said study co-author Andrew Capaldi, an associate professor in the UArizona Department of Molecular and Cellular Biology and BIO5 Institute member.
The Capaldi Lab is interested in determining how cells sense stress and starvation and then decide how fast to grow. Understanding how TORC1 is triggered in different organisms is important for developing treatments for a wide variety of diseases.

A new study by researchers in The Picower Institute for Learning and Memory at MIT provides evidence from both mouse models and postmortem human tissue of a direct link between two problems that emerge in Alzheimer’s disease: a buildup of double-stranded breaks (DSBs) in the DNA of neurons and the inflammatory behavior of microglia, the brain’s immune cells.
A key new finding is that neurons actively trigger an inflammatory response to their genomic damage. Neurons have not been known to signal the brain’s immune system in Alzheimer’s disease, said study lead author Gwyneth Welch, a former MIT Brain and Cognitive Sciences graduate student in the lab of senior author Li-Huei Tsai.
“This is a novel concept in neuroscience: the idea that neurons can be activating inflammatory activity in response to DNA damage,” Welch said. “The general idea was that neurons have a more passive relationship with microglia regarding age-associated neuroinflammation.”
Instead, what Welch, Tsai and co-authors report in Science Advances is that neurons coping with mounting DSBs go through stages of first trying to fix their fractured DNA and then, when it apparently fails, sending out via molecular signals to microglia, which responded by taking on a more inflammatory state. In experiments where the scientists interrupted the immune signaling, they prevented microglia from entering that state and degrading neural circuit connections, or synapses.
Members of Tsai’s lab have been studying DSBs in the context of Alzheimer’s for more than a decade. Tsai said the new findings add to the emerging understanding of the role they play in Alzheimer’s.
“We have a longstanding interest in understanding DNA breaks in neurons,” said Tsai, Picower Professor of Neuroscience and a founder of MIT’s Aging Brain Initiative. “We previously showed that DNA double stranded breaks are necessary for the induction of activity-regulated gene expression in neurons but we also observed profound DNA damage in neurons in the early stages of neurodegeneration.