Magenta Drops As FDA Issues Clinical Hold On Blood Cancer Candidate IND

 The FDA has instituted a clinical hold on Magenta Therapeutics Inc's 

MGTA Investigational New Drug Application (IND) of MGTA-117.

• In June, the IND was filed to initiate a Phase 1/2 trial of MGTA-117 in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
• The FDA has asked Magenta to develop an additional bioassay to be used in conjunction with the PK/PD model to inform dose escalation decisions in addition to safety monitoring. 
• The clinical hold does not relate to the toxicology or manufacturing of MGTA-117. 
• Magenta has initiated bioassay development. 
• The Phase 1/2 clinical trial of MGTA-117 is intended to evaluate its safety, pharmacokinetics (PK), and pharmacodynamics (PD) as a single agent in the relapsed/refractory AML and MDS patient population. 
• Magenta ended Q2 2021 with more than $200 million in cash sufficient to execute its existing plans.
• Magenta's MGTA-117 program is the Company's lead targeted conditioning product candidate, an antibody-drug conjugate (ADC) designed to deplete hematopoietic stem cells (HSCs) selectively.

https://www.benzinga.com/general/biotech/21/07/22080530/magenta-therapeutics-stock-drops-as-fda-issues-clinical-hold-on-blood-cancer-candidate-ind

KemPharm in U.S. Launch of Innovative ADHD Treatment

 KemPharm, Inc. (NASDAQ: KMPH), a specialty pharmaceutical company engaged in the discovery and development of proprietary prodrugs, today announced the U.S. commercial launch of AZSTARYS™, a once-daily product for the treatment of attention deficit hyperactivity disorder (ADHD) in patients age six years and older. Corium, Inc. (Corium), a portfolio company of Gurnet Point Capital (GPC), is leading the commercialization of AZSTARYS in the U.S.

AZSTARYS was approved by the U.S. Food and Drug Administration (FDA) in March 2021 and consists of serdexmethylphenidate (SDX), KemPharm’s prodrug of d-methylphenidate (d-MPH), co-formulated with immediate-release d-MPH. Subsequent to the approval of AZSTARYS, SDX was classified as a Schedule IV controlled substance by the U.S. Drug Enforcement Administration (DEA). AZSTARYS is classified as a Schedule II controlled substance as it includes a 70:30 mixture of SDX (Schedule IV) and d-MPH (Schedule II).

https://finance.yahoo.com/news/kempharm-announces-u-launch-innovative-123000105.html

J&J sees s $2.5 billion in global sales from Covid vaccine this year

 Johnson & Johnson said Wednesday it expects to sell $2.5 billion of its Covid-19 vaccine this year, even as concerns mount over the shot’s effectiveness against the delta variant.

In releasing its second-quarter financial results, the company also reported earnings and revenue that beat Wall Street’s expectations.

Here’s how J&J did compared with what Wall Street expected, according to average estimates compiled by Refinitiv:

• Adjusted EPS: $2.48 per share vs $2.27 expected.
• Revenue: $23.31 billion vs $22.21 billion expected.

The company’s share price was up nearly 1% in premarket trading following the report.

J&J’s pharmaceutical business, which developed the single-shot Covid vaccine, generated $12.59 billion in revenue, a 17.2% year-over-year increase.

The company’s consumer unit, which makes products such as Neutrogena face wash and Listerine, generated $3.7 billion in revenue, up 13.3% from a year earlier. Its medical device unit generated $6.9 billion, a 62.7% increase. That unit was hit hard last year as the pandemic forced hospitals to postpone elective surgeries and Americans stayed home.

“We’ve all realized over the last 18 months just how important good health is and elective isn’t elective forever,” J&J Chief Financial Officer Joseph Wolk told CNBC after the company released its earnings report Wednesday.

Global sales of the Covid vaccine in the quarter were $164 million.

The company raised its earnings and revenue guidance for the year. J&J now expects a full-year profit of $9.50 to $9.60 per share, compared with its previous forecast of $9.30 to $9.45 per share. It expects revenue between $92.5 billion and $93.3 billion, compared with its prior forecast of $89.3 billion to $90.3 billion.

The financial results come a day after a new study suggested the J&J vaccine is much less effective against the delta and lambda variants than against the original virus. Researchers are now suggesting that a booster dose may be needed for J&J recipients.

The study, which has not yet been peer-reviewed, is at odds with a report from the company, which found the shot is effective against delta, especially against severe disease and hospitalization, even eight months after inoculation.

Delta, the dominant variant in the U.S., now accounts for an estimated 83% of infections in the nation, according to the Centers for Disease Control and Prevention.

Wolk told CNBC Wednesday that people should be “guarded” about the new study, adding the results were based on blood samples in a lab and may not reflect the shot’s performance in a real world setting.

“I think it’s probably best for everyone to refer to health officials who have not yet recommended a booster, even for some less duration vaccines out there,” he said.

https://www.cnbc.com/2021/07/21/johnson-johnson-jnj-earnings-q2-2021.html

NBER: Recession Trough in April 2020

 From NBER: Business Cycle Dating Committee Announcement July 19, 2021

The Business Cycle Dating Committee of the National Bureau of Economic Research maintains a chronology of the peaks and troughs of US business cycles. The committee has determined that a trough in monthly economic activity occurred in the US economy in April 2020. The previous peak in economic activity occurred in February 2020. The recession lasted two months, which makes it the shortest US recession on record.

The NBER chronology does not identify the precise moment that the economy entered a recession or expansion. In the NBER’s convention for measuring the duration of a recession, the first month of the recession is the month following the peak and the last month is the month of the trough. Because the most recent trough was in April 2020, the last month of the recession was April 2020, and May 2020 was the first month of the subsequent expansion.

In determining that a trough occurred in April 2020, the committee did not conclude that the economy has returned to operating at normal capacity. An expansion is a period of rising economic activity spread across the economy, normally visible in real GDP, real income, employment, industrial production, and wholesale-retail sales. Economic activity is typically below normal in the early stages of an expansion, and it sometimes remains so well into the expansion.

The committee decided that any future downturn of the economy would be a new recession and not a continuation of the recession associated with the February 2020 peak. The basis for this decision was the length and strength of the recovery to date.
emphasis added

https://www.calculatedriskblog.com/2021/07/nber-recession-trough-in-april-2020.html

Spinal fluid biomarkers detect neurodegeneration, Alzheimer's in living patients

 Alzheimer's disease and related diseases can still only be confirmed in deceased patients' brains via autopsy. Even so, the development of biomarkers can give patients and their families answers during life: Alzheimer's disease can be accurately detected via peptides and proteins in a patient's cerebrospinal fluids (CSF), which can be collected through a lumbar puncture and tested while the patient is alive. In 2018, a new framework suggested combining three Alzheimer's disease biomarkers in CSF -- pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N), collectively called ATN. According to recent research from the Perelman School of Medicine at the University of Pennsylvania, the ATN framework can be extended to detect another neurodegenerative condition: frontotemporal degeneration.

Patients with frontotemporal degeneration can experience a range of symptoms, including behavioral changes, executive dysfunction, and language impairments. Distinguishing frontotemporal degeneration from Alzheimer's disease can be a challenge for clinicians: the symptoms of frontotemporal degeneration can sometimes overlap with Alzheimer's disease, and a subset of patients can even have both pathologies. Biomarkers can fill the gap by providing evidence of whether Alzheimer's pathology underlies a patient's symptoms.

"CSF biomarkers work similarly to a pregnancy test, offering a simple positive or negative result when enough of a substance is detected. But like a pregnancy test, biomarkers for Alzheimer's disease can provide false negatives or positives," said lead investigator Katheryn A.Q. Cousins, PhD, a research associate in the Frontotemporal Degeneration Center in the Department of Neurology at Penn Medicine. "Alzheimer's is a diverse disease, and it is common for other conditions to also be present in the brain. The ATN framework may provide a more complete look at a person's diagnosis and give us a much richer understanding of not only Alzheimer's disease, but other co-occurring neurodegenerative conditions. However, to accomplish this, additional biomarkers that can detect other neurodegenerative conditions are critically needed."

The findings, published in Alzheimer's and Dementia: The Journal of the Alzheimer's Association, show that ATN incorporating neurofilament light chain (NfL) may provide a more accurate and precise diagnosis for patients with frontotemporal degeneration. NfL is a protein abundant in the brain, whose levels increase as degeneration progresses. Cousins' work shows that CSF NfL may be a more accurate marker of neurodegeneration for patients with frontotemporal degeneration, including for Alzheimer's disease.

"While the ATN framework is very exciting and offers much opportunity for patients with Alzheimer's disease, these biomarkers don't capture every case of the disease. We want to be able to detect and treat every patient with neurodegenerative disease as early as possible, and more research is needed to fully understand how biofluids track with the disease process," said Cousins. "I am eager to conduct additional research into which patients might be missed by these markers, what they have in common, and what causes the pathological and clinical differences in the disease."

This study was funded by the Swedish Research Council (2018-02532); the European Research Council, (681712); Swedish State Support for Clinical Research (ALFGBG-720931); the Alzheimer Drug Discovery Foundation (201809-2016862); the Swedish Alzheimer Foundation, (AF-742881); European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236); and the Alzheimer's Association Research Fellowship (AARF-16-44368).

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Story Source:

Materials provided by University of Pennsylvania School of Medicine. Note: Content may be edited for style and length.

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Journal Reference:

1. Katheryn A.Q. Cousins, Jeffrey S. Phillips, David J. Irwin, Edward B. Lee, David A. Wolk, Leslie M. Shaw, Henrik Zetterberg, Kaj Blennow, Sarah E. Burke, Nikolas G. Kinney, Garrett S. Gibbons, Corey T. McMillan, John Q. Trojanowski, Murray Grossman. ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration. Alzheimer's and Dementia, 2021; 17: 822-830 DOI: 10.1002/alz.12233

https://www.sciencedaily.com/releases/2021/07/210720122354.htm

SARS-CoV-2: Achilles' heel of viral RNA

 Certain regions of the SARS-CoV-2 genome might be a suitable target for future drugs. This is what researchers at Goethe University, together with their collaborators in the international COVID-19-NMR consortium, have now discovered. With the help of dedicated substance libraries, they have identified several small molecules that bind to certain areas of the SARS-CoV-2 genome that are almost never altered by mutations.

When SARS-CoV-2 infects a cell, it introduces its RNA into it and re-programmes it in such a way that the cell first produces viral proteins and then whole viral particles. In the search for active substances against SARS-CoV-2, researchers have so far mostly concentrated on the viral proteins and on blocking them, since this promises to prevent, or at least slow down, replication. But attacking the viral genome, a long RNA molecule, might also stop or slow down viral replication.

The scientists in the COVID-19-NMR consortium, which is coordinated by Professor Harald Schwalbe from the Institute of Organic Chemistry and Chemical Biology at Goethe University, have now completed an important first step in the development of such a new class of SARS-CoV-2 drugs. They have identified 15 short segments of the SARS-CoV-2 genome that are very similar in various coronaviruses and are known to perform essential regulatory functions. In the course of 2020 too, these segments were very rarely affected by mutations.

The researchers let a substance library of 768 small, chemically simple molecules interact with the 15 RNA segments and analysed the result by means of NMR spectroscopy. In NMR spectroscopy, molecules are first labelled with special types of atoms (stable isotopes) and then exposed to a strong magnetic field. The atomic nuclei are excited by means of a short radio frequency pulse and emit a frequency spectrum, with the help of which it is possible to determine the RNA and protein structure and how and where small molecules bind.

This enabled the research team led by Professor Schwalbe to identify 69 small molecules that bound to 13 of the 15 RNA segments. Professor Harald Schwalbe: "Three of the molecules even bind specifically to just one RNA segment. Through this, we were able to show that the SARS-CoV-2 RNA is highly suitable as a potential target structure for drugs. In view of the large number of SARS-CoV-2 mutations, such conservative RNA segments, like the ones we've identified, are particularly interesting for developing potential inhibitors. And since the viral RNA accounts for up to two thirds of all RNA in an infected cell, we should be able to disrupt viral replication on a considerable scale by using suitable molecules." Against this background, Schwalbe continues, the researchers have now already started follow-up trials with readily available substances that are chemically similar to the binding partners from the substance library.

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Story Source:

Materials provided by Goethe University Frankfurt. Note: Content may be edited for style and length.

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Journal Reference:

1. Sridhar Sreeramulu, Christian Richter, Hannes Berg, Maria A Wirtz Martin, Betül Ceylan, Tobias Matzel, Jennifer Adam, Nadide Altincekic, Kamal Azzaoui, Jasleen Kaur Bains, Marcel J.J. Blommers, Jan Ferner, Boris Fürtig, M. Göbel, J Tassilo Grün, Martin Hengesbach, Katharina F. Hohmann, Daniel Hymon, Bozana Knezic, Jason Martins, Klara R Mertinkus, Anna Niesteruk, Stephen A Peter, Dennis J Pyper, Nusrat S. Qureshi, Ute Scheffer, Andreas Schlundt, Robbin Schnieders, Elke Stirnal, Alexey Sudakov, Alix Tröster, Jennifer Vögele, Anna Wacker, Julia E Weigand, Julia Wirmer-Bartoschek, Jens Wöhnert, Harald Schwalbe. Exploring the druggability of conserved RNA regulatory elements in the SARS‐CoV‐2 genome. Angewandte Chemie International Edition, 2021; DOI: 10.1002/anie.202103693

https://www.sciencedaily.com/releases/2021/07/210720122337.htm

Is bacterial acidity a key to tackle antimicrobial resistance?

 Decreasing bacterial acidity could help reduce antimicrobial resistance by eliminating bacteria that can survive being treated with antibiotics.

Scientists at the University of Exeter have developed a novel method, which allows users to measure the pH of individual bacteria before, during and after treatment with antibiotics.

The research, published in the journal mBio, lays the foundation for understanding the special properties of bacteria that survive being treated with antibiotics, so that new ways of targeting them can be developed.

The Exeter University research team found that even before antibiotic treatment, common infection causing Escherichia coli cells that can survive treatment have a more acidic intracellular pH compared to clonal cells that are eliminated by the antibiotic treatment. These surviving cells are called persisters because they are responsible for persistent bacterial infections and contribute to antibiotic resistance.

Antibiotic resistance is one of the most pressing public health challenges and threatens the ability to effectively fight infectious diseases, with around 10 million people predicted to die annually of infections by 2050.

The University of Exeter research team has discovered the mechanisms that permit persisters to have an acidic pH. By measuring the genetic properties of these cells, they found that two cellular processes, namely tryptophan metabolism and carboxylic acid catabolism, are responsible for the low pH measured in persister bacteria.

Dr Stefano Pagliara, a biophysicist in the Living Systems Institute, leading this research at the University of Exeter, said: "Our findings indicate that the manipulation of the intracellular pH represents a bacterial strategy for surviving antibiotic treatment. Our new data suggest a strategy for developing antibiotics that interfere with key cellular components of persisters and decrease their acidity."

The team is now working on expanding this research to find out whether cell acidity is key for antibiotic resistance in other critical bacterial pathogens such as Pseudomonas aeruginosa and Burkholderia pseudomallei and to identify drug molecules that can alter the pH of persister cells before antibiotic treatment.

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Story Source:

Materials provided by University of Exeter. Note: Content may be edited for style and length.

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Journal Reference:

1. Olivia Goode, Ashley Smith, Ashraf Zarkan, Jehangir Cama, Brandon M. Invergo, Daaniyah Belgami, Santiago Caño-Muñiz, Jeremy Metz, Paul O’Neill, Aaron Jeffries, Isobel H. Norville, Jonathan David, David Summers, Stefano Pagliara. Persister Escherichia coli Cells Have a Lower Intracellular pH than Susceptible Cells but Maintain Their pH in Response to Antibiotic Treatment. mBio, 2021; DOI: 10.1128/mBio.00909-21

https://www.sciencedaily.com/releases/2021/07/210720114429.htm