Quick COVID breathalyzer could allow mass screening in public places

 According to experts, bringing an end to the pandemic will require rapid screening of people attending large gatherings, such as conferences and weddings. Even those who are asymptomatic can still transmit COVID-19 to others, making it important to identify and isolate them until they are no longer contagious. Now, researchers reporting in ACS Nano have developed a prototype "breathalyzer" that can sensitively and accurately diagnose COVID-19, even in asymptomatic individuals, in less than five minutes.

Currently, the "gold standard" for COVID-19 testing is a technique called reverse transcription-polymerase chain reaction (RT-PCR), which is slow, requires an uncomfortable nasopharyngeal swab for sample collection and must be performed in a lab. The rapid antigen test is much quicker but has a higher rate of false negatives and positives. Scientists have also developed breathalyzer-type tests for COVID-19, which rely on differences in concentrations of volatile organic compounds exhaled by those infected with the coronavirus, but most require bulky, nonportable instruments for analysis. Xing Yi Ling and colleagues wanted to develop a quick, convenient and accurate breathalyzer test that would be suitable for on-site screening of large numbers of people.

The researchers designed a handheld breathalyzer that contains a chip with three surface-enhanced Raman scattering (SERS) sensors attached to silver nanocubes. When a person exhales into the device for 10 seconds, compounds in their breath chemically interact with the sensors. Then, the researchers load the breathalyzer into a portable Raman spectrometer that characterizes the bound compounds based on changes to the molecular vibrations of the SERS sensors.

The team found that Raman spectra from COVID-positive and -negative people were different in regions responsive to ketones, alcohols and aldehydes, which they used to develop a statistical model for COVID diagnosis. They tested the breathalyzer on 501 people in hospitals and airports in Singapore, who were shown by RT-PCR to be negative (85.2 percent), positive and symptomatic (8.6 percent), or positive and asymptomatic (6.2 percent) for the coronavirus. The method had a 3.8 percent false-negative and 0.1 percent false-positive rate, comparable to RT-PCR tests, but it could be completed on-site in less than five minutes. The breathalyzer could someday be a new tool to reduce the silent spread of COVID-19 in communities, the researchers say.

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Toward a COVID-19 breathalyzer for kids

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More information: Shi Xuan Leong et al, Noninvasive and Point-of-Care Surface-Enhanced Raman Scattering (SERS)-Based Breathalyzer for Mass Screening of Coronavirus Disease 2019 (COVID-19) under 5 min, ACS Nano (2022). DOI: 10.1021/acsnano.1c09371

https://phys.org/news/2022-02-quick-covid-breathalyzer-mass-screening.html

Immunological memory provides long-term protection against coronavirus

 Many questions about how exposure to SARS-CoV-2 by infection or immunization might result in long-term protective immunity remain unanswered. Onur Boyman, head of the Department of Immunology, and his research team at the University of Zurich and the University Hospital Zurich, have now taken a closer look at how this long-lived protection is formed. Together with researchers from ETH Zurich, they identified specific signaling pathways that determine when immune cells develop into so-called memory T cells.

From short-lived killers to long-term memory T cells

Virus-specific antibodies produced by B cells are insufficient to effectively protect against the novel coronavirus. The cellular immune response to SARS-CoV-2 is just as important. Here, virus-specific CD8+ T cells play a crucial role, as they can identify and kill the cells that have been infected by the virus. These cytotoxic T cells eliminate viruses that are hidden inside the host cells and help prevent the spread of millions of newly formed viruses. "These T cells are usually active for only a short time and disappear quickly. When it comes to establishing long-term protective immunity, it is important to generate long-lived memory T cells that are activated very quickly upon re-exposure to the virus," explains Onur Boyman. This latter ability is referred to as immunological memory.

Previous studies have focused on the whole CD8+ T cell population that formed in response to the virus. Boyman and his team have now succeeded in tracking individual clones of SARS-CoV-2-specific CD8+ T cells in patients with COVID-19, from the acute viral infection up to one year after recovery. The researchers were also able to identify the signaling pathways responsible for the transition of CD8+ T cells from short-lived killers to long-lived memory cells—and they found a distinct molecular signature.

Immune messengers determine the cell type

In their study, the researchers were able to demonstrate that the signature of long-lived memory CD8+ T cells was already present during acute SARS-CoV-2 infection, and these cells could thus be distinguished from their short-lived counterparts at an early stage. "The distinct signature of memory cells contained signals of immune messengers, such as interferons, which are an important part of the immune response against SARS-CoV-2 and also contribute to controlling viral infections," says Onur Boyman.

Immune response varies from one patient to another

The study reveals the complex way in which immunological memory to SARS-CoV-2 is—or is not—formed and maintained. While some infections result in robust and long-lasting T cell memory, others fail to do so. The newly identified signature makes it possible to determine which type of infection—e.g., mild or severe, systemic or limited to mucosal membranes—gives rise to sustained immunity. The immune response is also shaped by vaccines, which contain different ingredients and adjuvants. "While everyone responds differently to the virus or a vaccine, cellular immunity plays a crucial role in preventing severe cases of COVID-19 in both vaccinated and recovered people," says Boyman.

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B cells need the help of other memory cells to defend against chronic viruses

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More information: Sarah Adamo et al, Signature of long-lived memory CD8+ T cells in acute SARS-CoV-2 infection, Nature (2021). DOI: 10.1038/s41586-021-04280-x

https://medicalxpress.com/news/2022-02-immunological-memory-long-term-coronavirus.html

Anavex Responds to Rett Trial Controversy, Blames CRO

 On February 1, 2021, New York-based Anavex Life Sciences touted positive topline data from a Phase III AVATAR study of blarcamesione (Anavex 2-73) in adult females with Rett syndrome. The press release has been shrouded with controversy ever since, and the company’s stock fell 16% despite the seemingly optimistic results.

STAT News’s Adam Feuerstein began a series of tweets accusing the company of moving the goalposts on the study, starting with: “Anavex changed the primary and secondary endpoints of this Rett study on Jan. 18, allowing it to claim success when the drug most likely failed. This press release is entirely misleading.”

BioSpace contacted Anavex for a response. Andrew Barwicki, representing the company’s Investor Relations, provided the following statement: “RSBQ-AUC had been a pre-specified analysis from the beginning of the AVATAR study. The primary endpoint change was implemented before the database lock in the study, simultaneously also changing the study from a Phase II to a Phase III study incorporating guidance from the FDA. However, the administrative update on the clinicaltrials.gov website was not made on a timely basis by the CRO, leaving the inaccurate impression of a late change — which was factually not the case. We advise that Clincialtrials.gov website should not be relied upon — only direct communication from the company.”

Now some background. Rett syndrome is a rare neurological disorder primarily affecting girls. It results in severe problems with talking, walking, eating and potentially breathing. Severity varies, but it is not degenerative, and people affected can live to middle-aged or beyond.

Anavex reported that the drug demonstrated a statistically significant improvement compared to placebo for the primary efficacy endpoint as well as all secondary efficacy endpoints. The primary endpoint was RSBQ AUC (Rett Syndrome Behaviour Questionnaire). It showed a statistically significant and clinically meaningful improvement in 72.2% of patients compared to 38.5% in the placebo group. One of the secondary efficacy endpoints was ADAMS, a measure of emotional behavior symptoms.

The RSBQ is a rating scale of Rett syndrome behavior and determines patients’ neurobehavioral symptoms as they correlate to quality of life. This can include things like general mood, breathing difficulties, hand behaviors, repetitive facial movements and rocking of the body, along with others.

The secondary endpoints are also based on various ways of rating anxiety and emotional behavior. The company reported that 52.9% of patients taking the drug demonstrated improvement versus 8.3% on placebo.

What Feuerstein and other critics are pointing out is that two weeks ago, on January 18, Anavex changed the clinical trial from a Phase II to a Phase III and changed the endpoints, at least on the clinicaltrials.gov website.

Prior to the change, the company’s primary endpoint was biomarkers of plasma concentration at seven weeks as well as pharmacokinetic activity. In the shift, the biomarkers became secondary endpoints, and the behavioral evaluations became the primary endpoint.

In the press release, the company did not report on the laboratory biomarker measurements. However, the presentation did, noting that, “AVATAR efficacy endpoints demonstrated statistically significant and clinically meaningful reduction in Rett syndrome symptoms with related changes in potential biomarkers of disease pathology.”

Specifically, GABA was significantly increased and Gliotoxin L-alpha-aminoadipic acid (L-AAA) was significantly decreased.

The data presentation also indicated that an analysis of weekly seizure counts found that relative to placebo, the drug was linked to a 50.7% reduction in weekly seizure risk.

Anavex has since placed a large notice on its homepage: “IN RESPONSE TO PUBLIC COMMENTS AND FOR CLARIFICATION: The statements made by Adam Feuerstein from STAT News are false and untrue.” They also provided a link to a detailed presentation on the Phase III AVATAR study.

In an interview with Investor’s Business Daily, Anavex’s chief executive officer, Christopher Missling, called the controversy “an inaccurate impression.” He points out that the changes to the study were implemented in December 2021 and the website was only updated on January 18, 2022.

“The administrative updates on the website were not made on a timely basis by the CRO (clinical research organization), leaving the inaccurate impression of a late change, which was actually not the case,” Missling said.

He also said that the decision to select the RSBQ and the Anxiety, Depression and Mood Scale was made in December after all patients were enrolled but before the company had data on how the drug had performed.

“The misunderstanding was the information of the upgrade of the trial was done to this website at a late stage, giving the wrong impression that (the changes were) done at a late time,” Missling said.

Anavex’s decision to update the trial to Phase III was based on data from earlier trials, and that the new measures chosen provided a better idea of the drug’s benefit. In early January, at the JP Morgan Healthcare Conference, Anavex had described the trial as “pivotal,” a term typically used in the industry to describe a Phase III trial.

https://www.biospace.com/article/anavex-responds-to-rett-trial-controversy-blames-cro/

Regeneron, Sanofi Blockbuster Dupixent Scores Points in 5 More Indications

 Regeneron Pharmaceuticals and Sanofi's anti-inflammatory drug Dupixent (dupilumab) has shown to be effective against five types of type 2 inflammations, with more indications expected to surface soon. 

The five diseases include chronic spontaneous urticaria (CSU), eosinophilic esophagitis (EoE), atopic dermatitis, asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). 

Details of this pivotal data come from 18 abstracts, all pointing to evidence that the IL-4 and IL-3 pathways that Dupixent inhibits are what mainly cause the said diseases, thus adding to the growing body of work that supports these indications. A late-breaking discovery from two Phase III studies also highlights the drug's potential against prurigo nodularis. 

Further information will be revealed during the companies' presentation at the American Academy of Allergy, Asthma and Immunology annual meeting on February 25 to 28. Those who want to see each of the abstracts may view them in an online supplement to The Journal of Allergy and Clinical Immunology. 

Among the expected highlights of the upcoming AAAAI event are oral presentations on the different possible uses for Dupilumab, including for itch and hives reduction in patients with CSU, effects in adolescent and adult patients with EoE, long-term efficacy in asthmatic patients who are with or without comorbid chronic rhinosinusitis/nasal polyposis and in the prevention of seasonal asthma exacerbations.

Also to be highlighted in the presentations are the effects of Dupixent in patients with CRSwNP, the ability to improve quality of life in those diagnosed with chronic rhinosinusitis with nasal polyps and improvements in skin barrier functions in those with moderate-to-severe atopic dermatitis, among several others. 

Dupixent is a fully human monoclonal antibody created using Regeneron's proprietary VelocImmune technology. It is not an immunosuppressant and does not need laboratory monitoring. The drug currently has the go-ahead from Japan, Europe, the U.S. and other countries for atopic dermatitis, asthma and CRSwNP in different age groups. It is also approved for use in one or more of these mentioned indications in over 60 countries. 

The drug is the product of a global collaboration deal between Sanofi and Regeneron and has been evaluated in 60 clinical trials to date. The companies are currently running Phase II and Phase III clinical studies.

VelocImmune technology uses genetically engineered mouse models that have been endowed with genetically humanized immune systems, enabling the platform to create optimized, fully human antibodies. 

Aside from Dupixent, only a few therapies have succeeded in getting FDA approval for such types of antibodies, such as REGEN-COV (casirivimab and imdevimab), Kevzara (sarilumab), Praluent (alirocumab), Libtayo (cemiplimab-rwlc), Evkeeza (evinacumab-dgnb) and Inmazeb (atoltivimab, maftivimab and odesivimab-ebgn).

https://www.biospace.com/article/regeneron-sanofi-score-more-wins-for-dupixent-across-five-indications/

Lujàn out for next 4-6 weeks

 Sen. Ben Ray Lujàn (D-N.M.) is expected to return to the Senate within four to six weeks, barring complications, after suffering a stroke, aides confirmed to The Hill. 

The news of Lujàn’s potential return comes after his staff announced on Thursday that he had been hospitalized after suffering the stroke last week but is expected to make a full recovery. 

The first-term senator's absence shocked many of his colleagues, who appeared to learn the news through reporters.

In a 50-50 Senate, his time away also threatens to leave Democrats’ agenda in limbo until he returns.

Democrats still technically outnumber GOP senators for now because both Sens. Mitt Romney (R-Utah) and John Hoeven (R-N.D.) are absent because of the coronavirus.

However, both Hoeven and Romney are expected to return next week. 

Lujàn’s absence already caused Democrats to shuffle their schedule in the Commerce Committee, pulling three nominees who they will need Lujàn’s vote to confirm. 

Democrats will also need Lujàn to return in order to confirm a Supreme Court nominee unless whoever Biden nominates can pick up GOP support. Biden is expected to name someone by the end of the month. 

“All of us are hopeful and optimistic that he will be back to his old self before long,” said Senate Majority Leader Charles Schumer (D-N.Y.).  

“In the meantime, the U.S. Senate will continue to move forward in carrying out its business on behalf of the American people,” Schumer said.

https://thehill.com/homenews/senate/592543-lujan-out-for-next-4-6-weeks

A punch to the gut for Alzheimer's patients and their loved ones

 More than 6 million Americans suffering from Alzheimer's just received a gut-punch from the federal agency that oversees Medicare. So did their loved ones.

In mid-January, the Centers for Medicare and Medicaid Services made an unprecedented decision to cut off most seniors' access to an entire class of Alzheimer's treatments. CMS's actions will have a significant impact on dementia research — and could dash Americans' hopes for a cure. And this decision will hit vulnerable minority and other underrepresented populations especially hard.

The decision most immediately impacts Medicare enrollees who were considering Aduhelm, a medicine that the FDA approved in June. The drug reduces amyloid plaque in the brain, which many — but not all — scientists believe is a trigger for Alzheimer's.

The FDA's approval sparked debate — partly due to the drug's side effects and cost, but also due to concerns over its effectiveness. But the FDA weighed the science and determined that an accelerated approval — which the agency has used for promising treatments for HIV and cancer in the past — offered the best path forward. It gives patients, many of whom are hardest hit by a disease, access to a needed therapeutic option, while additional studies are done.

The bureaucrats at CMS evidently disagree with FDA scientists' approach, which has long been viewed as the gold-standard for science-based safety and efficacy standards.

The Medicare administrator announced it would restrict access to Aduhelm — and any other future "monoclonal antibodies that target amyloid for the treatment of Alzheimer's disease" — to a minuscule sliver of people enrolled in CMS-approved clinical trials, all of which could take several years. The proposal excludes millions of Medicare beneficiaries currently living with the disease, and it will impact people of color particularly hard.

Studies show that over the last two decades, even though minorities are at an increased risk of developing Alzheimer's, 94.7 percent of clinical trial participants for developmental Alzheimer's treatments have been white.

The announcement also has implications beyond Medicare. Commercial insurers typically mimic the agency's coverage decisions, so the pronouncement will adversely impact patients with mild cognitive impairment (MCI) and mild Alzheimer's who have private insurance.

The decision marks a significant setback for Alzheimer's research. Nearly 100 Alzheimer's programs have failed in the past decade. So the FDA's accelerated approval of Aduhelm, the first new Alzheimer's treatment since 2003, wasn't just hopeful news for patients; it was a historic event that gave researchers, and investors, confidence to continue plugging away in search of new treatments.

Today, there are companies of all sizes working to develop treatments to stop, prevent, or slow the progression of Alzheimer's using a variety of novel strategies. Small biopharma companies are leading the majority of these programs.

If Medicare — which pays for the vast majority of Alzheimer's treatment — won't cover a new drug, despite the FDA's experts ruling that the medicine has great potential, companies would be foolish to keep investing in risky, hugely expensive Alzheimer's research.

CMS officials are, in effect, setting themselves up as a second drug-approval agency. This sets a terrible and potentially far-reaching precedent. The staff at the FDA is approximately three times the size of the CMS. They are scientifically trained at judging the benefit and risk of drugs and have a long history of getting academic feedback. CMS is not equipped for this. They lack the expertise to tackle these scientific questions — and legally, the agency appears to have exceeded its authority.  

In its announcement, CMS made clear that it would only be satisfied by clinical trials of Aduhelm that are done under its own aegis, and that its determination to restrict access to the drug was the result of its own "thorough review process." These words and actions are a dangerous rebuke to the FDA's scientific autonomy and decision-making authority.

If unchallenged, this reproach — and this unilateral assertion of drug-evaluation powers — could harden into a precedent that could damage our treatment-approval process irreparably. And the onslaught of Alzheimer's and other difficult to treat diseases will continue unchecked for generations to come.

Michelle McMurry-Heath is a physician-scientist and president and CEO of the Biotechnology Innovation Organization.

https://thehill.com/changing-america/opinion/592544-a-punch-to-the-gut-for-alzheimers-patients-and-their-loved-ones

Zimmer cut to Neutral from Buy by UBS

 Target to $130 from $172

https://finviz.com/quote.ashx?t=ZBH