The FDA has granted Eisai full approval for Leqembi to treat adults with Alzheimer’s disease.
According to a press release from the regulatory agency, Leqembi (lecanemab, Eisai/Biogen) is the first amyloid-targeting antibody to be granted traditional approval after receiving accelerated approval.
The FDA approved Leqembi, an amyloid-targeting therapeutic, to treat adults with Alzheimer’s disease. Image: Adobe Stock
“Today’s action is the first verification that a drug targeting the underlying disease process of Alzheimer’s disease has shown clinical benefit in this devastating disease,” Teresa Buracchio, acting director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, stated in the release. “This confirmatory study verified that it is a safe and effective treatment for patients with Alzheimer’s disease.”
A humanized immunoglobulin gamma 1 monoclonal antibody that clears amyloid beta and removes amyloid plaques in the brain, Leqembi was approved as a 100 mg/mL IV dose and indicated for those with mild cognitive impairment or the mild dementia stage of AD.
“Alzheimer’s disease is a progressive, fatal disease that greatly impacts not only the people living with it, but also their loved ones, care partners and society,” Eisai CEO Haruo Naito, said in a joint press release from Eisai and Biogen.
Expressing his gratitude to those who have worked exhaustively towards an effective treatment for AD, Biogen President and CEO Christopher Viehbacher stated, “Today marks a breakthrough in the treatment of Alzheimer’s disease, and we are proud to be at the forefront of ushering in a new era of advances for a disease that was previously considered untreatable.”
In early June, the FDA Peripheral and Central Nervous System Drugs Advisory Committee unanimously ruled that Leqembi showed clinical benefit in early AD, roughly 5 months after the therapeutic was granted accelerated approval based on results of the CLARITY AD study, a phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial.
“Approval of Leqembi will serve as a catalyst for driving further developments and investments in the Alzheimer’s pipeline,” Howard Fillit, MD, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said in a foundation press release. “It is more important than ever to double down and widen our focus to developing the next generation of drugs based on the biology of aging that can lead to a combination therapy and precision medicine approach.”
Editor’s note: This article was updated July 7, 2023, to add information on the dosage of Leqembi as well as comments from Eisai and Biogen executives.
The traditional approval of Leqembi by the FDA is a big step in finding effective treatments for Alzheimer’s disease. Lecanemab-irmb becomes the first drug in its class to receive a traditional approval from the FDA. This approval process of lecanemab-irmb and the announcement by CMS confirming a broader coverage for the drug is great news for individuals with AD and their family members. This drug will now be more widely available for use among people with AD who desperately need more effective treatments. The traditional approval of lecanemab-irmb will also serve as a catalyst for pharmaceutical companies to invest in trials of newer classes of medications in order to find more effective treatments for a devastating illness like AD.
Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP
Professor and chair, department of psychiatry
Inaugural Bhatia Family Endowed Chair in Psychiatry
The FDA has approved Daybue for the treatment of Rett syndrome in patients aged 2 years and older, making it the first and only approved treatment for the genetic disorder, according to an Acadia Pharmaceuticals press release.
The approval of Daybue (trofinetide, Acadia) was based on safety and efficacy data from the phase 3 LAVENDER study, which enrolled 187 female patients with Rett syndrome aged 5 to 20 years. According to the release, trofinetide demonstrated significant improvement from baseline in Rett Syndrome Behavior Questionnaire and Clinical Global Impression-Improvement scores compared with placebo at week 12. The most common side effects were diarrhea (82%) and vomiting (29%).
Acadia Pharmaceuticals received FDA approval for its Rett syndrome treatment. Image: Adobe Stock
“As the first FDA-approved drug for the treatment of Rett syndrome, Daybue now offers the potential to make meaningful differences in the lives of patients and their families who have lacked options to treat the diverse and debilitating array of symptoms caused by Rett syndrome,” Acadia CEO Steve Davis, JD, said in the release. “We are grateful to all of the Rett syndrome patients, caregivers, clinical investigators and our employees who have contributed to making today a reality and look forward to getting Daybue to patients as quickly as possible.”
The FDA accepted the new drug application for trofinetide in September, and the drug is expected to be available in the United States by the end of April 2023, the company stated.
The FDA has cleared Abbott’s laboratory blood test for concussion, making it the first commercially available test of its kind, according to a company press release.
The Alinity i traumatic brain injury test measures two serum biomarkers that are closely associated with brain injury and provides results in 18 minutes. Those with a negative test would be able to avoid a CT scan and may be able to reduce their time waiting at a hospital, the release stated. The test can be used for adult patients within 12 hours of suspected injury.
FDA clears Abbott’s lab-based blood test to evaluate for concussion. Image: Adobe Stock
Because misdiagnosis of or undiagnosed TBI can exacerbate its short- and long-term effects, “providing tools that can objectively aid in the evaluation of a TBI or concussion is essential to giving people the answers and treatment they need,” the company said.
“People sometimes minimize a hit to the head, thinking it’s no big deal,” Beth McQuiston, MD, medical director in Abbott’s diagnostics business, said in the release. “Others wonder if a visit to the doctor or emergency room for a possible concussion will provide them with meaningful answers or care. Now that this test will be widely available in labs across the country, medical centers will be able to offer an objective blood test that can aid in concussion assessment. That’s great news for both doctors and people who are trying to find out if they have suffered a traumatic brain injury.”
According to Abbott, the Alinity i TBI test has a 96.7% sensitivity and complements the company’s i-STAT TBI plasma test, a rapid blood test for concussion previously cleared by the FDA in 2021.
Summary: Active compounds in the edible Lion’s Mane mushroom can help promote neurogenesis and enhance memory, a new study reports. Preclinical trials report the compound had a significant impact on neural growth and improved memory formation. Researchers say the compound could have clinical applications in treating and preventing neurodegenerative disorders such as Alzheimer’s disease.
Source: University of Queensland
Researchers from The University of Queensland have discovered the active compound from an edible mushroom that boosts nerve growth and enhances memory.
Professor Frederic Meunier from the Queensland Brain Institute said the team had identified new active compounds from the mushroom, Hericium erinaceus.
“Extracts from these so-called ‘lion’s mane’ mushrooms have been used in traditional medicine in Asian countries for centuries, but we wanted to scientifically determine their potential effect on brain cells,” Professor Meunier said.
“Pre-clinical testing found the lion’s mane mushroom had a significant impact on the growth of brain cells and improving memory.
“Laboratory tests measured the neurotrophic effects of compounds isolated from Hericium erinaceus on cultured brain cells, and surprisingly we found that the active compounds promote neuron projections, extending and connecting to other neurons.
“Using super-resolution microscopy, we found the mushroom extract and its active components largely increase the size of growth cones, which are particularly important for brain cells to sense their environment and establish new connections with other neurons in the brain.”
Researchers found lion’s mane mushroom improved brain cell growth and memory in pre-clinical trials. Credit: University of Queensland
Co-author, UQ’s Dr Ramon Martinez-Marmol said the discovery had applications that could treat and protect against neurodegenerative cognitive disorders such as Alzheimer’s disease.
“Our idea was to identify bioactive compounds from natural sources that could reach the brain and regulate the growth of neurons, resulting in improved memory formation,” Dr Martinez-Marmol said.
Dr Dae Hee Lee from CNGBio Co, which has supported and collaborated on the research project, said the properties of lion’s mane mushrooms had been used to treat ailments and maintain health in traditional Chinese medicine since antiquity.
“This important research is unravelling the molecular mechanism of lion’s mane mushroom compounds and their effects on brain function, particularly memory,” Dr Lee said.
The study was published in the Journal of Neurochemistry.
UQ acknowledges the collaborative efforts of researchers from the Republic of Korea’s Gachon University and Chungbuk National University.
Abstract
Hericerin derivatives activates a pan-neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory
The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity.
Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity.
Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA-12 only partly prevented the NDPIH-induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK-293T cells, an effect that was not sensitive to ANA-12 in the presence of TrkB.
Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with H. erinaceus crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory.
Hericene A therefore acts through a novel pan-neurotrophic signaling pathway, leading to improved cognitive performance.
Summary: Levodopa, a drug commonly prescribed for the treatment of Parkinson’s disease that increases dopamine in the brain was found to reverse the effects of neuroinflammation on the reward system and improve symptoms associated with depression.
Source: Emory University
An Emory University study published in Molecular Psychiatry shows levodopa, a drug that increases dopamine in the brain, has potential to reverse the effects of inflammation on brain reward circuitry, ultimately improving symptoms of depression.
Numerous labs across the world have shown that inflammation causes reduced motivation and anhedonia, a core symptom of depression, by affecting the brain’s reward pathways.
Past research conducted by the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine has linked the effects of inflammation on the brain to decreased release of dopamine, a chemical neurotransmitter that regulates motivation and motor activity, in the ventral striatum.
In the study, researchers demonstrated that levodopa reversed the effects of inflammation on the brain’s functional connectivity in reward circuitry and anhedonia (inability to feel pleasure) in depressed individuals with higher C-reactive protein (CRP), a blood biomarker produced and released by the liver in response to inflammation.
Levels of inflammation can be easily measured by simple blood tests, like CRP, readily available in clinics and hospitals throughout the U.S.
The study included 40 depressed patients with a range of CRP levels from high to low who underwent functional brain scans on two visits after receiving in random order either placebo or levodopa, a drug often prescribed for disorders like Parkinson’s disease.
Levodopa improved functional connectivity in a classic ventral striatum to ventromedial prefrontal cortex reward circuit but only in patients with higher levels of CRP. This improvement in reward circuitry in depressed individuals with higher CRP also correlated with reduced symptoms of anhedonia after levodopa.
Levels of inflammation can be easily measured by simple blood tests, like CRP, readily available in clinics and hospitals throughout the U.S. Image is in the public domain
“This research demonstrates the translational potential for use of inflammation-related deficits in functional connectivity and could have important implications for the future investigations of precision therapies for psychiatric patients with high inflammation,” says principal investigator and senior author Jennifer C. Felger, Ph.D., associate professor of psychiatry and behavioral sciences, Emory School of Medicine.
Felger says the study findings are critical for two reasons. First, they suggest depressed patients with high inflammation may specifically respond to drugs that increase dopamine.
Second, Felger says these findings also provide additional evidence that functional connectivity in reward circuitry may serve as a reliable brain biomarker for the effects of inflammation on the brain.
“Moreover, as the effect of levodopa was specific to depressed patients with higher inflammation, this functional connectivity may be used to assess the responsiveness of the brain to novel treatments that might be targeted to this subtype of depressed patients in future studies and clinical trials,” says Felger.
Abstract
Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study
Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships which may involve the impact of inflammation on synthesis and release of dopamine.
To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable unmedicated adult MDD outpatients enrolled to have a range of inflammation (as indexed by plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (double-blind, randomized order ~1-week apart).
The primary outcome of resting-state (rs)FC in a classic ventral striatum to ventromedial prefrontal cortex reward circuit was calculated using a targeted, a priori approach.
Data available both pre- and post-challenge (n = 31/40) established stability of rsFC across visits and determined CRP > 2 mg/L as a cut-point for patients exhibiting positive FC responses (post minus pre) to L-DOPA versus placebo (p < 0.01).
Higher post-L-DOPA FC in patients with CRP > 2 mg/L was confirmed in all patients (n = 40) where rsFC data were available post-challenge (B = 0.15, p = 0.006), and in those with task-based (tb)FC during reward anticipation (B = 0.15, p = 0.013).
While effort-based motivation outside the scanner positively correlated with rsFC independent of treatment or CRP, change in anhedonia scores negatively correlated with rsFC after L-DOPA only in patients with CRP > 2 mg/L (r = -0.56, p = 0.012).
FC in reward circuitry should be further validated in larger samples as a biomarker of target engagement for potential treatments including dopaminergic agents in MDD patients with increased inflammation.
Marriage was associated with a lower risk for dementia and mild cognitive impairment in later life, researchers reported in the Journal of Aging and Health.
“Earlier studies suggest that being married in later life protects against dementia, and that being single in old age increases the risk of dementia. We examine midlife marital status trajectories and their association with dementia and mild cognitive impairment,” Vegard Skirbekk, PhD, of the Norwegian Institute of Public Health, and colleagues wrote.
Marriage was associated with a lower risk for dementia and mild cognitive impairment in later life.Source: Adobe Stock
Skirbekk and colleagues evaluated six different marriage trajectories – unmarried, continuously divorced, intermittently divorced, widowed, continuously married and intermittently married – using multinomial logistic regression. They said they looked at marital status in the 4th to 6th decades of life “as opposed to a one-time ‘snapshot’ of marital status” as well as clinical dementia and mild cognitive impairment status after age 70 years.
Study participants were garnered through a general population sample that was linked to population registries (n = 8,706). The authors estimated relative risk ratios (RRR) and then used mediation analyses, which were adjusted for education, number of children, smoking, hypertension, obesity, physical inactivity, diabetes, mental distress, as well as having no friends in midlife.
According to the authors, 11.6% of all subjects were diagnosed with dementia, while 35.3% were diagnosed with mild cognitive impairment. They found the highest prevalence of dementia among the unmarried (14.1%) and the lowest among the continuously married (11.2%).
In addition, dementia prevalence was higher for those unmarried (RRR = 1.73; 95% CI, 1.24-2.4), continuously divorced (RRR = 1.66; 95% CI, 1.14-2.43) and intermittently divorced (RRR = 1.5; 95% CI, 1.09-2.06), compared with those who were continuously married, the researchers wrote.
According to a counterfactual scenario the authors created, in which all participants had the same risk of receiving a dementia diagnosis as those who were continuously married, there would be 6% fewer dementia cases overall, they wrote.
“Our study draws further attention to marital histories as a predictor of later-life cognitive impairment and the potential mediating roles of having children, health and social risk factors,” Skirbekk and colleagues wrote. “Information on the link between marital status and later-life cognition could be useful for individuals as they consider the benefits and costs of different family forms, although we highlight that our results do not allow us to identify causal effects.”
As the world continues to grapple with effects of the COVID-19 pandemic, individuals around the globe are still dealing with symptoms of SARS-CoV-2 infection for months, even years, after their initial infection.
Post-acute sequelae of COVID-19, more commonly referred to as long COVID, are defined by the CDC as a wide range of new, returning or ongoing health issues that people experience after being infected with SARS-CoV-2, the virus that causes COVID-19.
While there currently is no definitive reason as to why long COVID occurs in those who are infected with SARS-CoV-2, researchers throughout the United States have been studying its effects for more than a year. On Sept. 16, 2021, the NIH announced it was allocating nearly $470 million for the study of long COVID.
Jennifer A. Frontera
“Honestly, there are multiple reasons why people might have long-term symptoms, and it depends in part on how severe their initial COVID-19 course was,” Jennifer A. Frontera, MD, a neuro-critical care specialist at New York University Langone Health, told Healio. “People who were hospitalized or had low oxygen levels may have had very different pathologies from folks who did not require hospitalization.”
Headache, fatigue most common symptoms
In October 2022, in a study published in Brain, Behavior, & Immunity, researchers reported fatigue and headache were the most common long COVID symptoms. In addition, at least one neurological symptom was self-reported by 80% of patients included in the study.
Although the SARS-CoV-2 virus has been circulating for almost 2 full calendar years, experts are still researching how and why symptoms continue to linger, as well as the different areas of the body the virus affects. While COVID-19 is a respiratory infection, long COVID has prominently affected the central nervous system — and specifically the brain.
“Clearly, [long COVID] is not only a respiratory disease,” Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center and chief of research and education services at Veterans Affairs St. Louis Health Care System, told Healio. “It is a systemic disease that affects nearly every organ system, including the brain.”
All organs affected
In August 2021, in eClinicalMedicine, researchers published data from an international study that included thousands of patients from 56 countries who were infected with COVID-19. The authors reported more than 200 symptoms in every organ system that were associated with long COVID. Al-Aly reported similar findings in a study he co-authored in October.
According to Al-Aly, people who contract COVID-19 have a much higher risk for several prolonged symptoms, not only headaches and brain fog. He and researchers found increased risk for all types of strokes; cognition and memory conditions, such as Alzheimer’s disease; episodic disorders; sensory disorders; hearing and vision problems; loss of smell and taste; and conditions involving inflammation in the brain, such as encephalitis.
Al-Aly said he and colleagues approached the study thinking data would confirm suspicions that brain fog and fatigue were primary effects of long COVID on the brain. “But what we found is really much more profound than that,” he said. “There really are various neurologic abnormalities in people with SARS-CoV-2 infection. It is really spanning different domains of the neurologic system. That was quite the finding.”
Al-Aly, who has been on the forefront of long COVID research since the initial days of the pandemic in the U.S., said there are many hypotheses as to why COVID-19 can affect different organ systems in the body and ultimately create prolonged symptoms.
Vascular vs. inflammatory hypotheses
“The vascular hypothesis suggests that SARS-CoV-2 can interact with the endothelial lining of the blood vessels, which are actually present everywhere,” Al-Aly said. “[The virus can] irritate the endothelial lining, making that lining more prone to form clots or microclots.”
While this was one of several hypotheses Al-Aly spoke of, it is currently unknown whether any of them are true. Walter Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke, told Healio it may not be because COVID-19 is affecting the brain, but rather the body’s immune system.
“If you get the flu, the symptoms will appear and they are due to the fact that it is not the virus infecting the [body], but the virus and your immune system’s response to the virus that creates the circulating chemicals called inflammatory mediators, and they affect brain function,” Koroshetz said.
Koroshetz compared long COVID’s effects to that of individuals with rheumatoid arthritis, a chronic inflammatory condition. He said most people with rheumatoid arthritis also report similar fatigue symptoms.
“It’s some of the autoimmune disorders where your immune system is overactive,” Koroshetz said. “You will get these same symptoms of fatigue and these problems, in terms of processing speed. These conditions are thought to be that the inflammatory mediators are affecting brain function.”
Mental problems also occur
An additional concern surrounding long COVID is not a physical problem, but a mental one. With symptoms lasting for months at a time, to even more than a year, there are reported increases in depression and anxiety among individuals with lasting symptoms, Frontera said.
“Depression is probably bidirectional,” she said. “We know that people who have brain injury, like stroke or Parkinson’s disease or seizures, have high risks for depression. We know depression is driven by neurochemical imbalances or neurotransmitter imbalances in the brain, and that can be triggered by a primary brain injury. The neurochemical imbalances that manifest as depression can exacerbate certain symptoms.”
“Things like financial insecurity, food insecurity, social isolation, grappling with new disability, death of a loved one — these things all can impact a lot of the neurological symptoms and the ability for folks to recover after hospitalization,” she said.
Frontera noted it is important for clinicians to look at all aspects of a patient’s life, because some personal factors may affect the severity of specific symptoms.
“If there are environmental or socioeconomic structures that could be addressed by a social worker, or someone else who could offer the patient resources, that is important to keep in mind,” she said. “There are opportunities to help some of these people out, and treating some of the issues — like food insecurity or financial insecurity — can really go a long way towards ameliorating some of symptom pathology we see.”
The FDA has approved Pfizer’s Zavzpret, a calcitonin gene-related peptide receptor antagonist nasal spray to treat migraine with or without aura in adults.
According to a company press release, approval was based on results of two randomized, double-blind, placebo-controlled studies that established the safety, efficacy and tolerability profiles of the intranasal therapeutic. In these studies, Zavzpret (zavegepant) was superior to placebo on the co-primary endpoints of pain freedom and freedom from most bothersome symptoms at 2 hours post-dose. The drug also demonstrated pain relief as early as 15 minutes in a prespecified secondary endpoint compared with placebo.
The FDA has approved Pfizer’s novel nasal spray to treat migraine in adults. Image: Adobe Stock
“The FDA approval of Zavzpret marks a significant breakthrough for people with migraine who need freedom from pain and prefer alternative options to oral medications,” Angela Hwang,MBA, chief commercial officer and president of global biopharmaceuticals business at Pfizer, stated in the release.
Zavzpret was well-tolerated in these trials, per the release, with the most common adverse reactions of taste disorders, nausea, nasal discomfort and vomiting reported in at least 2% of trial participants. Hypersensitivity reactions, including facial swelling and urticaria, have also been reported.
According to Pfizer, Zavzpret is expected to be available in pharmacies in July 2023.
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