Annovis to launch mid-stage study of lead drug in Alzheimer’s and Parkinson’s

Thinly traded nano cap Annovis Bio (NYSEMKT:ANVS) rockets 100% premarket on increased volume in reaction to its announcement of Institutional Review Board (IRB) signoff for a 15-site Phase 2 clinical trial evaluating lead candidate ANVS401 in patients with early Alzheimer’s disease and early Parkinson’s disease.

The two-part study will enroll 68 subjects who will receive ANVS401, an inhibitor neurotoxic proteins tau and alpha-synuclein, for four weeks. Topline data should be available in Q1 2021.

https://seekingalpha.com/news/3589004-annovis-bio-on-go-to-launch-mid-stage-study-of-lead-drug-in-alzheimers-and-parkinsons

FDA approves Endo’s Qwo for treatment of cellulite

Endo International (NASDAQ:ENDP) has received FDA approval of QWO (collagenase clostridium histolyticum-aaes) for the treatment of moderate to severe cellulite in the buttocks of adult women. This is the first FDA-approved injectable treatment for cellulite.

QWO is expected to be available throughout the U.S. in Spring 2021.

https://seekingalpha.com/news/3588978-fda-approves-endos-qwo-for-treatment-of-cellulite

Evolus under pressure on potential barrier to Jeuveau sales in U.S.

Evolus (NASDAQ:EOLS) slumps 38% premarket after the Administrative Law Judge (ALJ) overseeing the United States International Trade Commission (USITC) released a Notice of Initial Determination for a case filed by AbbVie’s (NYSE:ABBV) Allergan and its Korean partner Medytox in January 2019 to block imports of Evolus’ and Daewoong Pharma’s Jeuveau, a rival to Allergan’s Botox wrinkle treatment.

This non-binding initial decision by the ALJ finds a violation of Section 337 of the Tariff Act of 1930.

“We strongly disagree with the initial determination and we look forward to the full Commission’s Final Determination targeted for November 6, 2020,” said David Moatazedi, President and CEO.

The company intends to petition the Commission to review the case on the grounds of an improper attempt to use the USITC as a means to litigate a dispute between two Korean competitors.

The trade secrets asserted by Allergan and Medytox have never been used in the U.S.

https://seekingalpha.com/news/3588975-evolus-under-pressure-on-potential-barrier-to-jeuveau-sales-in-u-s

Novavax scores $1.6B in funding from Operation Warp Speed

The OWS award funds large-scale manufacturing of NVX-CoV2373, Novavax’s (NASDAQ:NVAX) COVID-19 vaccine candidate including production of 100M doses starting in late 2020.

That includes a pivotal Phase 3 clinical trial with up to 30,000 subjects beginning in the fall of 2020. A Phase 1/2 clinical trial of NVX-CoV2373 in 130 healthy participants 18 to 59 years of age began in Australia in May.

Preliminary immunogenicity and safety results are expected at the end of July, and the Phase 2 portion to assess immunity, safety, and COVID-19 disease reduction is expected to begin thereafter.

https://seekingalpha.com/news/3588973-novavaxplus-20-after-scoring-1_6b-in-funding-from-operation-warp-speed

Age-related impairments reversed in animal model

Elderly people are more prone to infectious diseases as the function of their immune system continuously declines with progression of age. This becomes especially apparent during seasonal influenza outbreaks or the occurrence of other viral diseases such as COVID-19. As the efficacy of vaccination in the elderly is strongly reduced, this age group is particularly vulnerable to such infectious pathogens and often shows the highest mortality rate. In addition to the age-related immune decline aged individuals are commonly affected by frailty that negatively impacts quality-of-life. Even though the average life-expectancy for humans continuous to rise, living longer is often associated with age-related health issues.

Important role of belly fat in aging processes identified

Researchers from the Department for BioMedical Reserarch (DBMR) and the Institute of Pathology at the University of Bern as well as the University Hospital Bern (Inselspital) have set out to identify new approaches to improve health-span in a fast-growing aging population. For many years scientists speculated that chronic low-grade inflammation accelerates aging processes and the development of age-related disorders. An international team of researchers under Bernese guidance has now demonstrated that visceral adipose tissue, known as belly fat, crucially contributes to the development of chronic low-grade inflammation. Scientist around Dr. Mario Noti, formerly at the Institute of Pathology of the University of Bern and Dr. Alexander Eggel from the Department for BioMedical Research (DBMR) of the Universität of Bern reported that certain immune cells in the belly fat play and an essential role in regulating chronic low-grade inflammation and downstream aging processes. They could show, that these immune cells may be used to reverse such processes. The findings of this study have been published in the scientific journal «Nature Metabolism»and were further highlighted by a News and Views editorial article.

Belly fat as a source of chronic inflammation

The team around Dr. Noti and Dr. Eggel could demonstrated that a certain kind of immune cells, known as eosinophils, which are predominantly found in the blood circulation, are also present in belly fat of both humans and mice. Although classically known to provide protection from parasite infection and to promote allergic airway disease, eosinophils located in belly fat are responsible to maintain local immune homeostasis. With increasing age the frequency of eosinophils in belly fat declines, while the number of pro-inflammatory macrophages increases. Owing to this immune cell dysbalance, belly fat turns into a source of pro-inflammatory mediators accumulating systemically in old age.

Eosinophil cell therapy promotes rejuvenation

In a next step, the researchers investigated the possibility to reverse age-related impairments by restoring the immune cell balance in visceral adipose tissue. “In different experimental approaches, we were able to show that transfers of eosinophils from young mice into aged recipients resolved not only local but also systemic low-grade inflammation”, says Dr. Eggel. “In these experiments, we observed that transferred eosinophils were selectively homing into adipose tissue”, adds Dr. Noti. This approach had a rejuvenating effect on the aged organism. As a consequence, aged animals showed significant improvements in physical fitness as assessed by endurance and grip strength tests. Moreover, the therapy had a rejuvenating effect on the immune system manifesting in improved vaccination responses of aged mice.

Translating findings into clinics

“Our results indicate that the biological processes of aging and the associated functional impairments are more plastic than previously assumed”, states Dr. Noti. Importantly, the observed age-related changes in adipose immune cell distribution in mice were also confirmed in humans. “A future direction of our research will be to now leverage the gained knowledge for the establishment of targeted therapeutic approaches to promote and sustain healthy aging in humans”, says Dr. Eggel.

https://www.eurekalert.org/pub_releases/2020-07/uob-air070620.php

Compounds halt SARS-CoV-2 replication by targeting key viral enzyme

As the death toll from the COVID-19 pandemic mounts, scientists worldwide continue their push to develop effective treatments and a vaccine for the highly contagious respiratory virus.

University of South Florida Health (USF Health) Morsani College of Medicine scientists recently worked with colleagues at the University of Arizona College of Pharmacy to identify several existing compounds that block replication of the COVID-19 virus (SARS-CoV-2) within human cells grown in the laboratory. The inhibitors all demonstrated potent chemical and structural interactions with a viral protein critical to the virus’s ability to proliferate.

The research team’s drug discovery study appeared June 15 in Cell Research, a high-impact Nature journal.

The most promising drug candidates – including the FDA-approved hepatitis C medication boceprevir and an investigational veterinary antiviral drug known as GC-376 – target the SARS-CoV-2 main protease (M^pro), an enzyme that cuts out proteins from a long strand that the virus produces when it invades a human cell. Without M^pro, the virus cannot replicate and infect new cells. This enzyme had already been validated as an antiviral drug target for the original SARS and MERS, both genetically similar to SARS-CoV-2.

“With a rapidly emerging infectious disease like COVID-19, we don’t have time to develop new antiviral drugs from scratch,” said Yu Chen, PhD, USF Health associate professor of molecular medicine and a coauthor of the Cell Research paper. “A lot of good drug candidates are already out there as a starting point. But, with new information from studies like ours and current technology, we can help design even better (repurposed) drugs much faster.”

Before the pandemic, Dr. Chen applied his expertise in structure-based drug design to help develop inhibitors (drug compounds) that target bacterial enzymes causing resistance to certain commonly prescribed antibiotics such as penicillin. Now his laboratory focuses its advanced techniques, including X-ray crystallography and molecular docking, on looking for ways to stop SARS-CoV-2.

M^pro represents an attractive target for drug development against COVID-19 because of the enzyme’s essential role in the life cycle of the coronavirus and the absence of a similar protease in humans, Dr. Chen said. Since people do not have the enzyme, drugs targeting this protein are less likely to cause side effects, he explained.

The four leading drug candidates identified by the University of Arizona-USF Health team as the best (most potent and specific) for fighting COVID-19 are described below. These inhibitors rose to the top after screening more than 50 existing protease compounds for potential repurposing:

• Boceprevir, a drug to treat Hepatitis C, is the only one of the four compounds already approved by the FDA. Its effective dose, safety profile, formulation and how the body processes the drug (pharmacokinetics) are already known, which would greatly speed up the steps needed to get boceprevir to clinical trials for COVID-19, Dr. Chen said.
• GC-376, an investigational veterinary drug for a deadly strain of coronavirus in cats, which causes feline infectious peritonitis. This agent was the most potent inhibitor of the M^pro enzyme in biochemical tests, Dr. Chen said, but before human trials could begin it would need to be tested in animal models of SARS-CoV-2. Dr. Chen and his doctoral student Michael Sacco determined the X-ray crystal structure of GC-376 bound by M^pro, and characterized molecular interactions between the compound and viral enzyme using 3D computer modeling.

• Calpain inhibitors II and XII, cysteine inhibitors investigated in the past for cancer, neurodegenerative diseases and other conditions, also showed strong antiviral activity. Their ability to dually inhibit both M^pro and calpain/cathepsin protease suggests these compounds may include the added benefit of suppressing drug resistance, the researchers report.

All four compounds were superior to other M^pro inhibitors previously identified as suitable to clinically evaluate for treating SARS-CoV-2, Dr. Chen said.

A promising drug candidate – one that kills or impairs the virus without destroying healthy cells — fits snugly, into the unique shape of viral protein receptor’s “binding pocket.” GC-376 worked particularly well at conforming to (complementing) the shape of targeted M^pro enzyme binding sites, Dr. Chen said. Using a lock (binding pocket, or receptor) and key (drug) analogy, “GC-376 was by far the key with the best, or tightest, fit,” he added. “Our modeling shows how the inhibitor can mimic the original peptide substrate when it binds to the active site on the surface of the SARS-CoV-2 main protease.”

Instead of promoting the activity of viral enzyme, like the substrate normally does, the inhibitor significantly decreases the activity of the enzyme that helps SARS-CoV-2 make copies of itself.

Visualizing 3-D interactions between the antiviral compounds and the viral protein provides a clearer understanding of how the M^pro complex works and, in the long-term, can lead to the design of new COVID-19 drugs, Dr. Chen said. In the meantime, he added, researchers focus on getting targeted antiviral treatments to the frontlines more quickly by tweaking existing coronavirus drug candidates to improve their stability and performance.

Dr. Chen worked with lead investigator Jun Wang, PhD, UA assistant professor of pharmacology and toxicology, on the study. The work was supported in part by grants from the National Institutes of Health.

https://www.eurekalert.org/pub_releases/2020-07/uosf-chs070620.php

Non-alcoholic fatty liver disease may spur Alzheimer’s-like neuroinflammation

Research from University of South Carolina associate professor Saurabh Chatterjee’s laboratory in Environmental Health Sciences, Arnold School of Public Health, and led by Ayan Mondal, a postdoctoral researcher from the same lab, has revealed the cause behind the previously established link between non-alcoholic fatty liver disease (i.e., NAFLD, recently reclassified as metabolic associated fatty liver disease or MAFLD) and neurological problems. The link they discovered, the unique role of an adipokine (Lipocalin-2) in causing neuroinflammation, may explain the prevalence of neurological Alzheimer’s disease-like and Parkinson’s disease-like phenotypes among individuals with MAFLD.

The investigators, which include members of Chatterjee’s Environment Health & Disease Laboratory and researchers from across UofSC*, published their results in the Journal of Neuroinflammation, a pioneering journal in the field. These findings build on years of research conducted by the interdisciplinary team, which has unearthed previously unknown pathways and mechanisms between the liver and the gut microbiome with other parts of the body through their focus on how environmental toxins contribute to liver disease, metabolic syndrome and obesity.

MAFLD affects up to 25 percent of Americans and much of the global population – many of whom are unaware of their condition. Yet the effects of this silent disease are far-reaching, possibly leading to cirrhosis, liver cancer/failure and other liver diseases. The findings from the current study not only confirm the strong correlation between MAFLD and neuroinflammation/neurodegeneration that has been established by other recent research, but it explains how this happens.

“Lipocalin 2 is one of the important mediators exclusively produced in the liver and circulated throughout the body among those who have nonalcoholic steatohepatitis – or NASH – which is a more advanced form of MAFLD,” Chatterjee says. “The research is immensely significant because MAFLD patients have been shown to develop Alzheimer’s and Parkinson’s-like symptoms as older adults. Scientists can use these results to advance our knowledge in neuroinflammatory complications in MAFLD and develop appropriate treatments.”

Ninety percent of the obese population and 40 – 70 percent of those with type 2 diabetes appear to have MAFLD, according to the Centers for Disease Control and Prevention. In addition to overweight/obese status and diabetes, other risk factors include high cholesterol and/or triglycerides, high blood pressure and metabolic syndrome.

These individuals have a higher risk for having diseased livers, which are associated with increased lipocalin 2 – as found in the present study. The lipocalin 2 circulates throughout the body at higher levels, possibly inducing inflammation in the brain.

“Chronic neuroinflammation is a critical element in the onset and progression of neurodegenerative diseases, including Alzheimer’s disease,” says Prakash Nagarkatti, UofSC Vice President for Research and a member of the research team.

“Our study may help design new therapeutic approaches to counter the neuroinflammatory pathology in NASH but also in other related brain pathology associated with chronic inflammatory diseases,” adds Chatterjee.

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*Co-authors include Ayan Mondal, Dipro Bose, Punnag Saha, Sutapa Sarkar, Ratanesh Seth, Diana Kimono, Muayad Albadrani, Mitzi Nagarkatti, Prakash Nagaratti.

This work has been supported by National Institutes of Health Awards 2-P20-GM-103641-06 (Project 4), 1-P01-ES-028942-01(Tox Core), and P01-AT-003961 (Project 4) to S. Chatterjee; and P01-AT-003961, P20-551 GM-103641, to M. Nagarkatti and P. Nagarkatti.

https://www.eurekalert.org/pub_releases/2020-07/uosc-uhn070620.php