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

Becky McCall

June 02, 2021

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 Government’s 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.

Plugging a Gap

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 [Medicines and 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 can’t detect, you can’t 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 Activity at a Mechanistic Level

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. "It’s also necessary to have molecules that are as selective as possible so they don’t 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."

Candidate Antivirals Leading the Way – But Where to Find Trial Volunteers?

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. "It’s impossible to study all of these and take them forward so we’ve strategically prioritised those drugs which have the greatest chance of success. We’ve 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. 

Molnupiravir – Candidate Under Joint Development Between MSD and Ridgeback Biotherapeutics

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.

Clinical Trial Platforms to Assess Candidate Antiviral Drugs

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.

"Let’s 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 don’t 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. "It’s 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. "Don’t bet against the virus becoming resistant. Mutating is their core business and it’s 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 can’t 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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