The goal of deploying two new antiviral drugs to prevent and treat COVID-19 by year end, as set by the UK Government, might not be as far-fetched as it sounds, according to plans and trials already underway said experts in the fields of virology and pharmaceuticals at a media briefing last week.

To meet the Governments challenge, antiviral drugs active against SARS-CoV-2 would most likely be administered orally, intranasally or inhaled; already be at the phase 1 or 2 stage of development or beyond; be for short-term use only; and exhibit targeted anti-viral activity without adversely affecting other parts of the body, said Ruth McKernan, PhD, chair of the BioIndustry Association. "Any drug that has more complicated administration, or has longer use, will have too high hurdles to jump," she highlighted.

A handful of candidate drugs meet these criteria and include favipiravir, niclosamide, iota-carrageenan, and molnupiravir, among others.

Despite a successful vaccination programme in the UK, there remains a pressing need for antiviral drugs to plug the gap between those protected via vaccination and those in whom vaccinations are ineffective, vaccination is contraindicated, or who choose to opt out of vaccination. New variant escape from vaccine protection also presents a threat and is likely to persist for some time to come.

Most pharmaceuticals take around 15 years from concept to market, but this development time is approximately halved in antiviral drugs, said McKernan. "The making of antivirals, along with anti-bacterial drugs has a higher probability of success than most other pharmaceuticals."

She also noted that the availability of human challenge studies where volunteers are purposefully infected with SARS-CoV-2 for study purposes were "hugely enabling" and were key given that case numbers limited the availability of trial volunteers, although there remains the possibility of conducting trials in countries with higher incidence of COVID-19.

Speaking alongside McKernan was Dr Ian Hall, professor of molecular medicine, University of Nottingham. He explained that successful candidate drugs would need to take effect early in disease where the drugs would be more effective. "Essentially, administration would be community based, so as soon as a positive test confirms infection, or as a prophylaxis in people notified as having been in contact with a positive individual. Other likely users will be those who become infected via nosocomial spread in hospitals who often have worse outcomes due to other conditions, and subgroups such as patients with haematological malignancies who typically have worse outcomes."

McKernan added that here in the UK, with government support and enablement, vaccine development had provided a good example of how to expedite manufacturing and supply issues. "This is likewise important for antiviral drugs too. In addition, the MHRA [Medicinesand Healthcare products Regulatory Agency] has also shown how it can evaluate products efficiently. However, she drew attention to maintaining a good testing and contact tracing system. "Antivirals work best early on in disease. If you cant detect, you cant treat, so you need a very good testing system."

In April, the Government announced that it was establishing a new Antivirals Taskforce to identify and deploy innovative, home-based, COVID-19 treatments as early as this autumn. Treatments would be taken after testing positive or being exposed to COVID-19 and would be aimed at reducing transmission and speeding up recovery.

Last Thursday, Eddie Gray, previously president of the European Pharmaceutical Business at GlaxoSmithKline, and CEO of Dynavax Technologies, accepted the role as chair of the new COVID-19 Antivirals Taskforce. "I do think the antiviral programme and the story around antivirals is an important one and has a real contribution to make to the overall response to COVID, and I am looking forward to moving that programme forward," he told journalists in a briefing hosted by the Science Media Centre.

Antiviral agents exert activity at the virus level, potentially interfering at one or more mechanistic stages of viral infection, for example, how the virus enters the cell, amplifies, makes new proteins, repackages itself into new viral particles, or bursts out to infect other areas of the body.

McKernan explained that there are four key ways that an anti-SARS-CoV-2 drug might work, in principle. Firstly, a drug can stop the virus entering the cell by interfering with the two main receptors that permit viral entry the angiotensin-converting enzyme (ACE) 2 receptor and/or the serine protease TMPRSS2 used for S protein priming. Secondly, because the virus needs to make new proteins, drugs can target the protein synthesis pathway of the virus specifically. Thirdly, a drug can target enzymes involved in the assembly of new viral particles called protease inhibitors; and fourthly drugs can interfere with RNA synthesis.

Good laboratory-based assays are also needed to test whether the molecules work, McKernan pointed out. "Its also necessary to have molecules that are as selective as possible so they dont interfere with other processes of the human body, making them safe to use."

Safety is essential and preclinical safety studies cannot be rushed, she stressed. "The duration of drug treatment is instrumental in the assessment of safety. If the duration is 5 days to 2-weeks then the safety hurdles are lower than a drug designed for longer duration of use."

Prof Hall is chair of the UK COVID-19 Therapeutics Advisory Panel (UK-CTAP) antiviral sub-panel. UK-CTAP was set up to advance agents most likely to be effective against COVID-19.

He explained that UK-CTAP had overseen 300 approaches with candidate drugs to tackle COVID-19. "Its impossible to study all of these and take them forward so weve strategically prioritised those drugs which have the greatest chance of success. Weve made 15 recommendations to the CMO [Chief Medical Officer] for trials in COVID-19."

The three leading recommendations are: favapiravir, an antiviral drug used for influenza and similar viruses; niclosamide (an oral antihelminthic drug used to treat tapeworm infections and which has shown activity against SARS-CoV-2 in vitro); and iota-carrageenan (a seaweed derivative and nasal spray shown to reduce symptoms of cold and flu, which has demonstrated in vitro activity against SARS-CoV-2).

UK-CTAP has considered 150 agents that currently have insufficient evidence to advance to existing clinical platforms, explained Prof Hall.

He also identified a significant challenge going forward. "To take these drugs forward through clinical trials we need to test them on patients with COVID-19. But since the vaccine strategy has been so successful to date the number of cases available is low and without sufficient cases then it is difficult to prove efficacy and pick up rare side effects."If we see escape variants it would be easier to do trials but the need for these drugs would be greater," he added.

Also in the race is molnupiravir (MK4482), a novel antiviral agent being jointly developed by pharmaceutical companies MSD and Ridgeback Biotherapeutics in the phase 3 MOVe-OUT Study.

"Molnupiravir inhibits a critical step in the replication of SARS-CoV-2, other coronaviruses and multiple RNA viruses. Early phase 2 studies show activity against SARS-CoV-2 and we believe it has potential to be a broad spectrum antiviral drug effective against a range of diverse coronaviruses as well as influenza and RSV [respiratory syncytial virus]," said Dr Daria Hazuda,vice president research, chief scientific officer, MSD.

Preclinical models suggest it can block transmission of SARS-CoV-2. Hazuda explained that based on results of a phase 2 study, the phase 3 trial will now focus on outpatient use because the highest efficacy impact on disease was seen in early community-based infection. Results are expected later in 2021.

The Prophylactic Therapy in Care Homes (NIHR-PROTECT-CH) trial platform is assessing two potential antiviral compounds in one of the most vulnerable population groups. PROTECT-CH will recruit 9300 residents across 300 UK care homes.

"Lets remember that 30-50% of COVID-19 deaths have occurred in care homes, but care homes are a highly neglected area of research," remarked Dr Philip Bath, professor of stroke medicine, University of Nottingham and lead researcher for PROTECT-CH.

Prof Bath explained that most virus enters the home with staff, relatives, or friends. Despite an effective vaccination campaign, a back-up and additional plan involving antiviral drugs is needed to prevent and treat cases in care homes. "Our vaccines are around 90% effective against the Wuhan variant but may be less so for the Kent and Indian variant, while reduction of transmission is only around 50%," he said, stressing that "vaccines dont work for everyone, and around 8% of residents and 15% of care home staff are not vaccinated".

Two antiviral drugs versus a control group will be assessed in the PROTECT-CH trial with the aim of preventing hospitalisation and mortality. The names of the trial drugs remain confidential currently, but they both have antiviral and anti-inflammatory activity, one is given by inhaler and the other intranasally.

PROTECT-CH takes a post-exposure prophylaxis approach. "We wait for a confirmed infection in the care home before randomisation (cluster randomisation of the whole care home) and treatment," explained Prof Bath, adding that as a platform, new interventions can be added over time.

The primary outcome is comprised of four-levels: no SARS-CoV-2 infection; SARS-CoV-2 infection but resident remains in care home; hospitalisation, and death.

Saye Khoo, professor of pharmacology and therapeutics, University of Liverpool, also runs a platform in the early phase trial area. He is chief investigator for the AGILE Coronavirus Drug Testing Initiative.

AGILE is in the early phase space up to phase 2 of drug development. "[The programme] takes a lot of potential candidates and advances the most plausible at speed and with rigour," he said. "Its an umbrella off which hang various trials of candidate drugs being tested at the same time. It is largely tuned to look at antiviral drugs mainly the game-changers to advance quickly and reject others."

He added that, "Vaccines do the bulk of heavy-lifting, but antivirals are important in managing the disease."

Prof Khoo drew attention to the threat of antiviral resistance without careful use. "Dont bet against the virus becoming resistant. Mutating is their core business and its how they survived for millions of years. We want to get ahead of this virus."

Prof Hall suggested that combination therapies might help prevent the development of resistance. "We have seen viruses develop resistance to other antiviral drugs. For example, by altering their genetic code, an antiviral becomes resistant to protease inhibitors as seen with hepatitis C or HIV, and here we use a combination of two or three drugs to help overcome that. It is currently, a theoretical risk in the long-term in the same way as we see variants escape from the vaccine."

Hazuda agreed but added that resistance was less likely when using an antiviral for an acute infection compared to use in a patient with chronic disease. "But we cant bet against a virus. When we start a drug development programme, it is in our interest to understand the potential for resistance."

Based on a briefing at the Science Media Centre, London, given on Thursday 27 May, 2021.

Smith and Jones report no relevant financial relationships. OR

Smith reports receiving grant funding from Merck. Jones reports no relevant financial relationships. The study was funded by Merck.

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Headway in the Challenge to Develop Two Antivirals Against COVID-19 This Year - Medscape

Samples from a study suggesting the coronavirus was circulating outside China by October 2019 have been re-tested at the World Health Organization's (WTO) request, two scientists who led the Italian research said. There is growing international pressure to learn more about the origins of the pandemic that has killed more than 3 million people worldwide and U.S. President Joe Biden last week ordered his aides to find answers.

The WHO said on Friday experts were preparing a proposal on the next studies to be carried out into the origins of the virus, but that there was no set timeline. The UN body reacted to Biden's announcement that intelligence agencies were pursuing rival theories, including the possibility of a laboratory accident in China, by saying the search was being "poisoned by politics".

COVID-19 was first identified in the central Chinese city of Wuhan in December 2019, while Italy's first patient was detected on Feb. 21 last year in a small town near Milan. However, a study published last year suggested antibodies to either the virus or a variant were detected in Italy in 2019.

That prompted Chinese state media to suggest the virus might not have originated in China, although the Italian researchers stressed the findings raised questions about when the virus first emerged rather than where. "The WHO asked us if we could share the biological material and if we could re-run the tests in an independent laboratory. We accepted," Giovanni Apolone, scientific director of one of the lead institutions, the Milan Cancer Institute (INT), said.

The WHO's request has not previously been reported. "WHO is in contact with the researchers that had published the original paper. A collaboration with partner laboratories has been set up for further testing," a WHO spokesman said.

The spokesman said the WHO was aware that the researchers are planning to publish a follow-up report "in the near future". He said the UN agency has contacted all researchers who have published or provided information on samples collected in 2019 that were reported to have tested positive for SARS-CoV-2, but does not yet have the final interpretation of the results.

The Italian researchers' findings, published by the INT's scientific magazine Tumori Journal, showed neutralising antibodies to SARS-CoV-2 in blood taken from healthy volunteers in Italy in October 2019 during a lung cancer screening trial. Most of the volunteers were from Lombardy, the northern region around Milan, which was the first and hardest hit by the virus in Italy.

"None of the studies published so far have ever questioned the geographical origin," Apolone told Reuters. "The growing doubt is that the virus, probably less powerful compared to later months, was circulating in China long before the reported cases," Apolone added.

DUTCH TEST The WHO chose the laboratory of the Erasmus University in Rotterdam for the re-test, Emanuele Montomoli, co-author of the original study and professor of Public Health at the Molecular Medicine Department in the University of Siena, said.

The Erasmus University did not reply to requests for comment. Italian researchers sent the team in Rotterdam 30 biological samples from October-December 2019 that they had found positive, 30 samples from the same period they had tested negative and 30 samples from as far back as 2018, negative.

"We sent them blind, that means our colleagues did not know which samples were positive and which negative," Apolone said. "They rechecked our samples with commercial tests, which are much less sensitive than the ones we devised and validated," Montomoli said.

Despite the differences in the two detection methods, both Italian scientists said they were satisfied with the results, delivered to them in late February, adding that they could not comment further until the team of Italian and Dutch scientists have published their findings. "We did not say in our study that we could establish without a doubt that the coronavirus, later sequenced in Wuhan, was already circulating in Italy in October," Montomoli said.

"We only found the response to the virus, namely the antibodies. So we can say that this coronavirus or a very similar one, perhaps a less transmissible variant, was circulating here in October," he added.

(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)

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IRVINE, Calif. & AMSTERDAM--(BUSINESS WIRE)--Agendia, Inc., a world leader in precision oncology for breast cancer, announced today that an oral presentation at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting revealed new data from the national FLEX registry that identify differences in tumor biology between ethnic groups that can lead to meaningful treatment decisions, reinforcing the need for appropriate representation of diverse patient populations in breast cancer studies.

A major theme of this years ASCO meeting centers around disparities in care and outcomes, which Agendias FLEX study aims to combat by prospectively enrolling 30,000 patients from various ethnicities, ages and demographic groups representative of the total breast cancer population. The data presentation from this study, Disparities within Luminal breast cancer: clinical and molecular features of African American and non-Hispanic White patients, delivered by first author of the study Kent Hoskins, MD, Co-Leader of the Breast Cancer Research Group and Director of Cancer Genetics at the University of Illinois Cancer Center, details significant biological differences in luminal breast tumors from African American and non-Hispanic White women, suggesting that shared adverse socioeconomic exposures and/or genetic ancestry may be driving disproportionately aggressive tumor biology in African American women. This finding further underscores the need for inclusion of diverse patient groups in clinical trials to ensure equity in drug development.

The data presented at ASCO 2021 show significant transcriptomic differences between Luminal tumors from African American and non-Hispanic White patients, seen even more starkly as our study controlled for age, obesity, and genomic classification, said Dr. Hoskins. The data show ER+ breast cancers in African American women more often had upregulation of the mTOR pathway and cell cycle genes, which require different treatment approaches than other ER+ breast cancers. These data tell us that we desperately need proper representation of diverse populations in clinical trials, and future studies focused on the efficacy of these agents specifically in African American women with breast cancer, so that all patients can benefit from precision medicine, tailored to them, and accounting for their ancestry and genomic profiles.

Additional data from Agendia regarding breast cancer in African American women was shared in an abstract titled Genomic risk classification by the 70-gene signature and 21-gene assay in African American, early-stage breast cancer patients. This study was triggered by recent research showing less accurate prognostic performance of OncotypeDX in African American women with early stage breast cancer. The abstract compared MammaPrint and OncotypeDX results in a cohort of African American women with ER+ breast cancer, and observed an overall discordance of 51% between the two tests in African American patients; notably, of tumors with a TAILORx intermediate risk score (11-25), 61% were classified as MammaPrint High Risk. Combined with previously published data in African American patients, 57% of OncotypeDX low risk score tumors are re-classified as MammaPrint High Risk, suggesting that OncotypeDX results could be less accurate in African American patients.

In addition, recent data indicate that African American patients who receive a low or intermediate OncotypeDX risk score have higher recurrence rates and lower survival than Caucasian patients with early stage breast cancer with the same risk score, a difference that can have meaningful clinical implications and requires further investigation.1

It is essential that genomic tests either work consistently across diverse groups of patients, or have the ability to be calibrated to do so, said Patricia Robinson, MD, Associate Professor of Hematology and Oncology at Loyola University Medical Center, and Assistant Dean of Diversity, Equity and Inclusion at the Strich School of Medicine, We cannot be using genomic tests that work for some people and not others, or accepting that the tests, which offer such crucial information, work better for some than for others. While the clinical evaluation of the discrepancy between OncotypeDX and MammaPrint may be ongoing, this data still captures the diversity of pathways driving tumor metastasis, and reinforces the importance of proper representation in trials and in test development and optimization.

Agendias large-scale, prospective FLEX registry continues to highlight data from real-world practices in one of the most flexible and inclusive studies in breast cancer research to date, playing an important part in the companys mission to help guide the diagnosis and personalized treatment of breast cancer for all patients throughout their treatment journey.

About Agendia

Agendia is a precision oncology company headquartered in Irvine, California, committed to bringing patients with early stage breast cancer and their physicians the information they need to make the best decisions for the full treatment journey. The company currently offers two commercially-available genomic profiling tests, supported by the highest levels of clinical and real world evidence, that provide comprehensive genomic information that can be used to identify the most effective breast cancer treatment possible for each patient.

MammaPrint, the 70-gene breast cancer recurrence assay, is the only FDA-cleared risk of recurrence test backed by peer-reviewed, prospective outcome data and inclusion in both national and international treatment guidelines. BluePrint, the 80-gene molecular subtyping assay, is the only commercially-available test that evaluates the underlying biology of a tumor to determine what is driving its growth. Together, MammaPrint and BluePrint provide a comprehensive genomic profile to help physicians make more informed decisions in the pre- and post-operative treatment settings.

Agendia develops evidence-based novel genomic tests and forges partnerships with groundbreaking companies to develop next-generation digital treatment tools. The ongoing research builds an arsenal of data that improve patient outcomes and support the evolving clinical needs of patients with breast cancer and their physicians every step of the way, from initial diagnosis to cancer-free.

Agendias assays can be ordered on core biopsies or surgical specimens to inform pre- and post-operative treatment decisions. For more information on Agendias assays and ongoing trials, please visit http://www.agendia.com.

1 Hoskins, Kent F., et al. Association of Race/Ethnicity and the 21-Gene Recurrence Score With Breast CancerSpecific Mortality Among US Women. JAMA Oncology, vol. 7, no. 3, 2021, p. 370., doi:10.1001/jamaoncol.2020.7320.

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ASCO 2021 Podium Presentation on Agendia FLEX Study Shows Clinical & Molecular Differences in Tumors of African American and Caucasian Patients...

Medical researchers say within a few years major breakthroughs in blood testing technology that use immune system response and genetic analysis to identify disease quickly and cost-effectively will be on the market.

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One morning last May, Tayah Fernandes's mother Shannon realized her four-year-old daughter was seriously unwell, and rushed her to the nearest ER in the English city of Manchester. The coronavirus had crashed onto Britain's shores weeks earlier, and emergency doctors were initially uncertain how best to treat Tayah's constellation of symptoms, which included stomach pains and a bright red rash.

They gave her antibiotics for a suspected bacterial infection, but her condition only worsened, her fever spiking. For her parents, for any parents, this was the ultimate medical nightmare; doctors in the dark for days over the cause of their daughter's illness.

Eventually, after further blood tests, physicians decided Tayah was suffering from an unusual inflammatory syndrome that pediatric infectious disease specialists had only just started to see, but suspected had links to Sars-COV-2.

Young patients across the U.K. and U.S. were arriving in intensive care units with symptoms similar to another disease doctors already recognized, called Kawasaki. But they had no guarantee that the same course of treatment injecting a solution of donors' antibodies into the bloodstream would prove successful.

In Tayah's case the antibodies solution, known as immunoglobulin, worked, to her parents' relief. But at around that same time last May a team of researchers at Imperial College, London confirmed through complex analyses of blood samples, taken from patients like Tayah, that this was indeed a new disease, distinct from Kawasaki.

A related breakthrough in that same laboratory, focused specifically on the way individual genes behave, could have seismic implications for a multi-billion dollar diagnostics sector that has received unprecedented attention from patients, regulators and the business world over the course of this pandemic.

A new method for identifying a specific illness from blood samples relies on the correlation between the activity in small set of genes, which represents the immune response, and specific pathogens that cause a specific disease just as the poliovirus causes polio, the coronavirus (SARS-COV-2, a pathogen) causes Covid-19. Scientists believe that by studying a small number of genes, they can quickly discern which pathogen is in a patient's system, what disease they have, and so how best to treat them.

Companies from small research university spin-offs to industry giants like Abbott Laboratories and Danaher's Cepheid are looking to build on two decades of research into the way our own immune systems naturally respond to foreign substances in our bodies, including pathogens like bacteria or viruses. A current technology like Cepheid's GeneXpert technology is able to distinguish between the different RNA of various viruses, such as SARS-COV-2, or a particular influenza strain, but experts say it's become increasingly clear that our body's immune systems can be faster, more accurate detection systems.

Historically, doctors have had to rely on a patient's case history and symptoms to narrow down the cause of an illness and develop a treatment plan. More recently, laboratory inspections at the molecular level such as the Cepheid technology have allowed clinicians to identify specific pathogens in nasal mucus, throat swabs or blood samples that might have caused an illness. But hunting for bacteria or a virus in this way can be time-consuming, costly and sometimes simply ineffective. The specific RNA signature of a virus can be hard to detect.

Abbott and Cepheid did not respond to requests for comment.

The team at Imperial College, London, working separately but at the same time as several counterparts around the world, are now convinced that future diagnoses can soon be conducted using table-top tests that will take just a matter of minutes.

These tests would not explicitly screen for a specific pathogen, but instead, allow scientists and medical professionals to simply watch how specific genes in the body are behaving as an indication of how an immune system is already responding to a pathogen that may not be easily otherwise detectable.

Imperial College professor Mike Levin currently leads an ongoing European Union-funded study focused on this potential, called "Diamonds." In recent years he and other scientists have shown how the observed activity in a small number of our genes can work as a kind of shorthand for our body's immune response to a pathogen. If a handful of specific genes out of thousands in a blood sample are seen to be activated or the opposite, inhibited it can indicate that a person is preparing to fight off a specific pathogen.

We think this is a completely revolutionary way of doing medical diagnosis.

Imperial College professor Mike Levin

Levin and colleagues already have a proof of concept for this diagnostic approach after studies involving thousands of patients with fever caused by tuberculosis, and hundreds of Kawasaki patients. And his Imperial College team's work with the "Diamonds" study are starting to bear fruit and could helpidentify the distinct immunological markers of illnesses like the coronavirus-linked multi-system inflammatory syndrome in children like Tayah Fernandes, now commonly known as MIS-C.

When Covid-19 turned up in multiple locations, with MIS-C in its wake, it presented Levin and his researchers with an unprecedented opportunity to test this technique on an entirely new disease.

In the future, these tests by relying on huge amounts of data and machine learning should be able to produce multi-class rather than just binary results. This means they could confirm not only if a pathogen is bacterial or viral, or whether someone has a specific disease or not, but could distinguish which one of a multitude of illnesses is afflicting their patient.

In short, Levin expects that by examining the behavior of a relatively small number of genes, clinicians will be able to assign patients to all the major disease classes within an hour.

"We think this is a completely revolutionary way of doing medical diagnosis," Levin said. He expects the research will provide the basis for new technology, but has no financial interest in any business related to it.

Rather than what he calls the "stepwise process" of first eliminating bacterial infections, treating for the most common conditions, and then doing more investigation, "this idea is the very first blood test can tell you, has the patient got an infection or not an infection, and what group of infection that is, right down to the individual pathogens."

Purvesh Khatri, an associate professor at the Stanford Institute for Immunity, Transplantation and Infection and Department of Medicine, says our immune systems have been evolving for millennia to combat pathogens, and so it may prove more effective, and efficient, to examine the response of our bodies.

"We didn't have a technology, until now, that could measure a set of genes in a rapid point of care way," he said. "But in the last couple of years, there have been enough technologies available that now allow us to measure a few genes in a rapid multiplex point of care assay way."

While neither the FDA nor any European regulators have approved these kinds of gene-based pathogen detection systems, Khatri, who is helping launch a related commercial venture, says they're coming soon. "In the next year or two, there will be several that will be available on the market."

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