The march of the anti-virals

Here comes the cavalry – or maybe not. Could anti-viral drugs cure Covid-19 and stem the tide of the pandemic? Will Big Pharma succeed? How long will it take? Victor Hill is asking – and not getting good answers.

Each man’s death diminishes me,
For I am involved in mankind.
Therefore, send not to know
For whom the bell tolls,
It tolls for thee.

– John Donne (1572-1631), For whom the bell tolls

A glimmer of hope?

Readers may have heard over the last few days that the daily death tolls from Covid-19 in Italy, Spain, France and the UK have peaked. But if you plot them you see not so much a bell curve as a panorama of the Himalaya, with jagged peaks and troughs across a desolate horizon, and no clear trend. Then we are invited to consider that the number of new cases of Covid-19 (i.e. people who have been tested and proved positive) might be about to decline – and, of course, there is generally a time lag of 10-14 days between the diagnosis and the fatality. But that could be optimistic.

As I wrote here last week, there is a lot going on inside the data; and this week we understand much better that we shall only fully understand that data once the war against this virus is finally over. If anything, the picture has become more confusing as the death toll intensifies. It is very lumpy – with hotspots such as (East) London, New York City and the delightful city of Bergamo in Lombardy. Yet there is more evidence emerging that the ultimate mortality rate for Covid-19 is no more than that of seasonal flu – even if, for those who succumb, it is a malign and sometimes hideous malady which has laid low even our own prime minister.

It also has emerged since last week that in the UK and in France people dying of Covid-19 in care homes were not even included in the figures. And I wrote last week that at least we can count the dead. Apparently, I was wrong. As figures have been revised, so the mortality rates in both countries have risen accordingly.

But there are reasons for hope. Early results from the Italian bio-laboratory Meleam suggested that 38 percent of a random (though admittedly small) sample of 1,731 Italians tested across nine regions have been exposed to the virus already. If valid, then that study would substantiate Professor Sunetra Gupta’s University of Oxford study (cited last week in my piece) which conjectured that half the population of the UK has already been exposed to the virus and therefore most (?) have immunity.

If scientific opinion shifts in this direction then the lockdowns could be lifted sooner rather than later. In the meantime, let me give you a sneak peek of a Special Report that James and I have been writing which will be out just after Easter. A significant analysis from Deutsche Bank Research based on the Hubei province data suggests that the lockdown will last in the UK until 23 May. That would represent a two-month partial hibernation of the economy – the consequences of which, while survivable, will endure for years.

In the meantime, the Government’s daily coronavirus press conference last Friday (03 April) signalled a new focus. Namely: the search for anti-viral medications which might alleviate the symptoms, if not cure, Covid-19. President Trump has been vociferating, sometimes confusingly, on this theme too.

Current treatments

According to New Scientist this week[i], the only treatments we have now for people with Covid-19 are supportive therapies. These are fluids, painkillers and fever reducers, and antibiotics to treat opportunistic bacterial infections. Those with seriously impaired lung function require ventilators which enable them to breathe under sedation. (Ventilators can do long-term damage, by the way.) All of these measures buy time to keep a person alive until their immune system gains enough strength to suppress the virus.

To give our bodies a better chance, drug researchers are pursuing three main strategies. The first is to use anti-viral medications to stop or slow the virus’s ability to replicate itself. Reducing the amount of the virus (viral load) in the metabolism makes symptoms less severe. The second strategy is to identify antibodies – the proteins our immune systems produce in response to an infection – that work against the virus and to use them to fight it. And third is to prevent auto-immune responses. That is another thing I learnt this week: that it is sometimes our own immune system which kills us.

Anti-virals

About 90 anti-virals have been approved since 1963, when Idoxuridine was authorised for the treatment of herpes. Most are only effective against a single type of virus. That makes it hard to repurpose them against new viruses. Because viruses rely on their host to survive, it is challenging to create drugs that kill viruses without harming humans too.

One possible anti-viral to combat Covid-19 could be Ivermectin, a widely-used, FDA-approved anti-parasitic treatment. A recent report in the journal Antiviral Research provides an account of a recent laboratory experiment where Ivermectin produced a 5000-fold reduction in the Covid-19 viral load.

An 09 April article in The Wall Street Journal points to 140 experimental drug treatments and vaccines under development which are not likely to exceed the demonstrable viral-killing effect of Ivermectin – which was first approved for human use in 1987 under the brand name Mectizan. Other anti-viral candidates include Ribavirin and Interferon.

Whatever happened to Tamiflu?

Some of us can remember the pandemic that never happened – that was the SARS (Severe Acute Respiratory Syndrome) epidemic of 2005 which swept across China and much of South East Asia but which, mercifully, did not ravage Europe and America as many feared it would. Back in 2005, pharmacies in the UK were encouraged to stock up on Tamiflu which was considered the best anti-viral available. I distinctly remember meeting a pharmacist at a social event back then who told me that he had a secret stock.

Oseltamivir, (discovered by Gilead but now out-of-patent) sold under the brand name Tamiflu, is an anti-viral medication used to treat and prevent influenza. Many medical organizations recommend it for people who have complications or are at high risk. The US Centers for Disease Control and Prevention recommends that clinicians use their discretion to treat those at lower risk within the first 48 hours of symptoms with Tamiflu. It is taken orally, either as a pill or liquid.

Since the ugly head of this pandemic first reared, I haven’t heard a single mention of Tamiflu in any media. If any of our well-informed readers can enlighten me – please get in touch. It’s baffling.

Remdesivir (Gilead)

Gilead Sciences (NADAQ:GILD) began working on Remdesivir back in the first decade of this century as a catch-all anti-viral and it was used widely to combat Ebola in Africa in the 2015 epidemic. On Wednesday last week (01 April) it was announced that the drug will be trialled imminently in 15 centres across the NHS. The first patients are currently being recruited for the trials which will take place in Liverpool, Manchester, London, Hull, Lancaster, Plymouth, Glasgow and Edinburgh. Trials are also taking place in the United States on patients who became infected with Covid-19 on board the Diamond Princess.

Remdesivir is a broad-spectrum anti-viral which has been demonstrated to protect animals against SARS and MERS which, like Covid-19, are coronaviruses. It works by disrupting the genetic code of a virus so as to prevent it replicating.

Demand for Remdesivir is already so high that Gilead recently had to stop providing access for people outside clinical trials. But, frustratingly, we still don’t know for sure if Remdesivir works against the new coronavirus. Optimists think that four large clinical trials evaluating Remdesivir in the US, combined with trials in China, might give preliminary results possibly as soon as the end of this month.

Hydroxychloroquine

President Trump is upbeat about Hydroxychloroquine, a treatment for malaria (thus an anti-malarial). It has been mooted by some as a possible cure for Covid-19. French doctors have been trialling it at Paris’s Pitié-Salpêtrière Hospital – but so far, according to Bloomberg, the results have not been encouraging[ii].

On Monday (06 April) it was reported that India was considering a request by Donald Trump to release stocks of Hydroxychloroquine which Mr Trump called a game-changer in the fight against Covid-19. Reportedly, the President called Indian Prime Minister Narendra Modi last Sunday, a day after India had banned the export of the drug which India manufactures in large quantities. The Indian media suggested this week that Mr Modi’s government is now considering supplying the drug to the US.

Hydroxychloroquine is related to chloroquine – one of the oldest and best-known anti-malarial drugs. President Trump previously claimed that the US Food and Drug Administration (FDA) had approved the medication for treating coronavirus – a claim the FDA later denied. Mr Trump later said that it had been approved for compassionate use – meaning that a doctor can prescribe a drug that is yet to be cleared by the government to a patient in a life-threatening condition.

Unfortunately, the malaria parasite has become highly resistant to Hydroxychloroquine with the result that its use has been discontinued in some jurisdictions. But in early February a study led by researchers at the Wuhan Institute of Virology in China (where else?) showed that they stimulate some antiviral activity in human cells.

Another issue. The incidence of Covid-19 is dramatically lower in malarial countries than in non-malarial ones, according to Dr Roy Spencer, a principal research scientist at the University of Alabama Huntsville. He compared Covid-19 cases versus malaria incidence by country in a statistical model and found a “stunning correlation”. Of course it is possible – if not likely – that countries in sub-Saharan Africa have under-reported the incidence of Covid-19. It is also possible that Covid-19 does not survive as easily in hot countries (the Wuhan epidemic started in mid-winter and spread to Northern Italy during its coldest month). But the most encouraging possibility is that those countries whose populations have been heavily exposed to the cheap, generic, anti-malarial drug chloroquine phosphate may have developed a high degree of immunity.

Existing vaccinations – BCG?

Angus Dalgleish, Professor of Oncology at St. George’s University, London, has suggested that certain medications currently used in the treatment of cancer could be used in the fight against Covid-19[iii]. A mycobacterial product by the catchy name of IMM-101 has proved in trials to be effective in the treatment of melanoma and pancreatic cancer. Professor Dalgleish reports that patients to whom he has administered this remedy have become apparently immune to colds and flu, even though they were previously susceptible. He proposes that NHS workers on the coronavirus front-line should be provided with shots of IMM-101 to boost their immunity.

IMM-101 shares properties with the BCG vaccine which protects against tuberculosis. Cells stimulated by IMM-101 include secrete cytokines which are known to kill viruses. And there is some inconclusive evidence emerging that countries which have had comprehensive BCG vaccination programmes such as Japan are demonstrating lower mortality rates from Covid-19. In contrast, Italy and Spain have never had comprehensive BCG vaccination programmes. Interestingly, the UK had a wide-scale BCG vaccination programme (this writer remembers being inoculated around 1970) but it was later curtailed, partly because the BCG jab can cause ulcers and infections at the injection site.

Generating antibodies

Biotech start-up AbCellera, based in Vancouver, succeeded in identifying all the antibodies in a blood sample taken from someone who had recovered from Covid-19. AbCellera has identified 500 antibodies – amongst millions – which seem to work against Covid-19. It is now working with Eli Lilly (NYSE:ELI) to develop an antibody-based therapy for Covid-19 “within months”.

A similar approach is being taken by the New York drug company Regeneron (NADAQ:REGN) which says it hopes to start mass producing the most potent antibodies identified by mid-April. Testing, however, takes time to determine if the treatments are effective and safe.

Last month, the Bill & Melinda Gates Foundation launched the Covid-19 Therapeutics Accelerator, which will contribute up to $125 million to speed up new drug development. The aim is to ensure drugs are priced so that people who need them will be able to get them, regardless of income. That is admirable – if idealistic.

But how long will it take? I don’t know and the experts don’t seem to know either. One thing I do know is that when this is all over there is going to be one Hell of a reckoning with Big Pharma.

***

In medieval England peasants were summoned from the fields by the solemn cadence of a tolling church bell, signalling to all that one of their number had just passed. The funeral and burial would take place immediately – just as in the case in Muslim lands today. Graves were unmarked in those days – only princes had tombs. Many English churches have stood for nearly a thousand years; and the yew tree in the churchyard is often older than the church itself because churches were built on druidic sites that held the yew tree sacred[iv]. But there are precious few gravestones in England dating from before 1750.

Death has always been a leveller. Those peasants understood perfectly that while we are all on different journeys, we all share the same final destination.

***

I call it the epidemic of conviviality. In my tiny corner of the universe (not representative of anything, I know) everybody is being so nice to one another. Digitally, of course.

My closest chum from my Oxford days sends me photos of his burgeoning tomato plant from his pile in Sussex on a daily basis. My amazing big sister in France, who has not been out for weeks, so protective is she of her septuagenarian husband, sends poems to her little brother. Never were so many ecstatic emojis mobilised online for a more noble purpose – namely, of keeping those collective peckers up, globally.

There is a lot wrong with digital addiction. But, overall, we should be thankful to Mr Zuckerberg at this testing time. We might never be allowed to kiss or hug our loved ones again: but at least we can still make them laugh.

Happy Easter/ Pesach, everybody – or just have a great long weekend in splendid isolation (hopefully with added sunshine). And stay well.

[i] See: https://www.newscientist.com/article/mg24532760-900-coronavirus-treatment-what-drugs-could-work-and-when-can-we-get-them/

[ii] See: https://www.bloomberg.com/news/articles/2020-04-02/hyped-malaria-drug-not-showing-much-effect-at-one-paris-hospital?fbclid=IwAR20gvFJzqeiuTuEnB7v7KiJ1q37jGFZ5qwxfMVlzrqt7tYfQLM3PBS3X3I

[iii] Could this be the answer to defeating corona? Daily Telegraph, 31 March 2020

[iv] The oldest yew tree in Britain is considered to be that in the churchyard at Fortingall, Perthshire, Scotland. It is estimated to be between 2,000 and 3,000 years old.