Gordon Campbell on the use of existing drugs to reduce the effects of coronavirus

smallerversionSo now, we’re all getting up to speed with the travel bans, the rigorous handwashing and drying, the social distancing, and the avoidance of public transport wherever possible. Right. At a wider level…so far, the public health system has proved itself able to cope with coronavirus cases still in single digits and with testing still in the low hundreds. Obviously, if and when the pandemic arrives in full force, it remains to be seen whether our test –and-tracing regimes will be robust enough to detect and isolate all the potential carriers. Logic would suggest not.

At the other end of the process – do we have anything like enough ventilators to cope with the large numbers of people that the virus will seriously affect ? Also, probably not. It would be interesting to know just how many ventilators (in total) our 20 District Health Boards possess between them. Finally there’s a question mark over how long the heroic medical staff in our health system can be expected to work under such intense pressure. (Probably, not for as long as the pandemic is likely to last.) Care will need to be rationed.

Reportedly, a coronavirus vaccine that’s able to protect individuals and communities from infection and transmission is still 18 to 24 months away. The focus in the meantime has to be on mitigation, by using the available tools. Can some of our existing drugs impede the virus from proceeding to its most serious/fatal outcomes? There are scattered reports on what relief can be provided by drugs such as – for instance – those used to inhibit the body’s inflammatory responses among the victims of arthritis. Any evaluation of this country’s preparedness should be including a national stock-take of such medications.

The following list of examples doesn’t claim to be exhaustive. Readers should also be aware that the research on re-purposing the existing array of drugs to combat coronavirus has to be treated with caution because (a) much is still unknown about the nature of the coronavirus and (b) the reports of fresh trialling in a Covid-19 context might well contain an element of Big Pharma seeking to recoup profits from this bout of re-purposing.

That aside, there is a genuine scientific rationale for why some existing anti-inflammatory drugs may be helpful – particularly in reducing the incidence and severity of the so called ‘cytokine storm’ phase of the body’s reaction, in which the immune system dangerously over-reacts to the invading virus.

Critically important studies emerging from China suggest that for many patients who die of Covid-19, it may be their own immune system, rather than the virus itself, that deals the fatal blow. This is called a cytokine storm. During a cytokine storm, an excessive immune response ravages healthy lung tissue, leading to acute respiratory distress and multi-organ failure. Untreated, cytokine storm syndrome is usually fatal. Over the past two decades, much has been learned about the diagnosis and treatment of cytokine storm syndromes. On the front lines of the Covid-19 response, it is critical that medical professionals are aware of the syndrome and prepared to identify and treat it.

To aid the early detection of potential cytokine storm reactions occurring further down the track, it is being suggested that the testing of patients presenting with high fevers should also include a serum ferritin test :

All Covid-19 patients sick enough for hospitalization should be given a cheap, quick, and readily available serum ferritin blood test. Indeed, elevated serum ferritin values have recently been reported in Chinese hospitalized patients with Covid-19. This is a good first screening tool for the possibility of a cytokine storm syndrome in sick patients with high fevers. The question then remains how best to treat a cytokine storm syndrome once it is identified.

One dauntingly broadstroke response might be to use very high doses of corticosteroids. However, targeted potential options are also being transposed from the rheumatoidal and oncologic contexts, focussing on drugs that inhibit the front-line protein mediators and receptors (such as : interleukin-1 (IL-1), IL-6, IL-18, and interferon gamma) that normally govern the body’s reaction to incoming infections, and which may prevent them (in the context of a cytokine storm) from indiscriminately attacking and damaging healthy tissue in for example, the lungs.

Here are some existing drugs currently coming under intense scrutiny :

1.Remdesivir. This experimental drug was originally developed to combat the ebola virus, and has been identified as a potential useful treatment for coronavirus. In order to be effective, it needs to be administered as early as possible in the infection cycle :

Remdesivir attacks the virus’s ability to replicate in the body and in animal studies has worked against two more deadly coronaviruses, Sars and Mers, particularly when it is given soon after symptoms appear. It has also shown promise when used against a wider variety of coronaviruses, including those that cause the common cold, and others that infect bats and pigs.

The same replication process occurs in all coronaviruses, raising hopes that if the drug works on one, it will work on all. “For this to be useful you have to really catch the virus as it’s ramping up replication in someone’s body and not after too much damage has been done,” said Sheahan. “If you can intervene prior to the virus topping out, there’s a pretty good chance you can improve outcomes and potentially save people’s lives. For Sars and Mers, in upper airway, virus peaks a week to 10 days after the onset of symptoms, so you probably have five to 10 days to intervene after you start to feel crummy.”

Trials of remdesivir are under way in China, and in the US :

Gilead Sciences’ investigational remdesivir has so far been viewed as the most promising drug against COVID-19. The drug’s being studied in two clinical trials in China’s Hubei province, the epi-centre of the outbreak. The National Institute of Allergy and Infectious Diseases is leading one [trial] in the U.S. And Gilead just initiated two additional phase 3 trials with plans to enroll about 1,000 patients, mainly in Asian countries.

Chinese firms have already begun to copy remdesivir, one good sign of its probable efficacy.

2. Actemra While remdesivir works by attacking the ability of the virus to replicate, other drugs – as mentioned – seek to suppress the potential for the immune system to over-react to the presence of the virus. The use of Roche’s drug Actemra was greenlit here by Pharmac in 2014, as a rheumatoid arthritis treatment. It has now emerged in the coronavirus context as a potentially effective inhibitor of the receptor for interleukin-6, normally a key agent in the body’s inflammatory resistance to infection :

Actemra doesn’t directly kill the novel coronavirus, now dubbed SARS-CoV-2. It’s known as an inhibitor of the receptor of interleukin 6 (IL-6), a pro-inflammatory cytokine. In the disease COVID-19, the body may respond to the pathogen by overproducing immune cells and their signaling molecules in a dangerous phenomenon called cytokine storm. Similar lung inflammation happened in SARS patients during the 2003 outbreak, mainly in China.

USTC [China] scientists and other research groups have recently fingered IL-6 as a main culprit in the[cytokine storm] immune overreaction among COVID-19 patients, hence the Actemra clinical trial. In 2017, the FDA also greenlighted Actemra to treat cytokine release syndrome—a form of cytokine storm—caused by CAR-T treatment [for leukemia.]

3. Kevzara The French drug company Sanofi also has rights to another IL-6 inhibitor on the global market. Kevzara is an example of the process mentioned earlier, whereby a drug that failed to live up to its original commercial expectations, is now being re-purposed to earn its keep for Big Pharma :

The drug was developed and approved under a collaboration between the drugmakers, but it hasn’t been a commercial star on the market. The trial preparations are the latest example of biopharma companies either racing to develop new medicines or repurposing existing medicines against the novel coronavirus…. It follows a move by Gilead to explore whether its antiviral remdesivir, originally developed to fight Ebola, can fight the infection. The company kicked off two phase 3 studies late last month. Gilead’s drug has already been deployed in Washington state, which has been fighting a cluster of cases, CDC director Robert Redfield said Tuesday. Numerous other drugmakers are developing drugs and vaccines….. Sanofi is working with the U.S. government on a vaccine…

To repeat: while a vaccine that’s able to offer immunity to the disease is still a long way off, these medications currently available appear to mitigate the effects, and thus serve to reduce the number of fatal outcomes. Here’s how a recent overview of the current rate of progress concludes:

Gilead has started phase 3 studies of remdesivir in COVID-19 patients while federal health officials and others conduct their own studies….In Japan, the drug was given to some American cruise ship passengers who “were probably going to die in a short amount of time,” an NIH doctor told the Wall Street Journal; none had died two weeks later. Aside from that medicine, the experts don’t believe existing HIV meds will be “viable therapies’…They do, however, see a rationale to explore whether ACE inhibitors or angiotensin receptor blockers could help fight the infection. The experts said a monoclonal antibody therapy might reach the market “even before a vaccine..”

Clearly, Pharmac and the Health Ministry need to be reporting to the officials currently planning our national coronavirus response about (a) what access, if any, does New Zealand have to remdesivir (b) how big our stockpiles of Actemra and Kevzara may be and (c) to what extent our frontline medical staff are being advised about when and how to use these medications.

Outside the hospital, prevention and slowing the rate of transmission has to be the priority. Inside the hospital, mitigation has to be the priority, using all the treatment tools that can be obtained, and brought to bear.

Covid-19 singalong

Hate to do this to you, but Covid-19 can be sung to the same tune as ‘Come On Eileen” by Dexy’s Midnight Runners…