Category: Anti-viral drugs

An effective drug that could treat a person once infected with Covid-19 and prevent the potential serious consequences would clearly dramatically reduce the impact of the pandemic. Indeed, if there was a very effective and very safe drug, we wouldn’t need to worry about a new vaccine!  It is also reasonable to ask that as new vaccines have been developed within 12 months from start to finish, can we be similarly optimistic about new treatments?

Do we actually need a new drug?

• As the Christmas panto season happens (or not this year!), what does the story of Aladdin tell us about prospects of new drugs for Covid-19?
• At the beginning of the pandemic there was an important question to be asked about treating Covid-19: “Can any drugs already licensed for treating other viral infection or indeed other diseases, be successful against Covid-19?”
• In technical terms – can we repurpose existing drugs rather than the much longer and risker process of developing new drugs?

In this post, I review where we are up to in repurposing and point out the challenges in starting to develop completely new drugs.

What do we want an antiviral drug to do for Covid-19?

• There are two ways any antiviral drug might work- by preventing
  • the virus multiplying once it enters a human cell
  • the damage after the virus has multiplied resulting in part as a consequence of the  body’s defence mechanisms 
• As the second of these  is common to a whole range of  infections (and indeed immune diseases like rheumatoid arthritis), repurposing a range of existing drugs was worthwhile trying in Covid-19
• The best example of this was the trial of the steroid dexamethasone, which has significantly cut the death rate of seriously ill Covid-19 patients

• The rest of this post will focus on specific antiviral drugs to stop the virus multiplying. 
• These could then be given to people in the community at the first signs of infection
• How likely is it that there are such existing drugs that could do this for Covid-19?

What examples are there of drugs that stop other viruses multiplying?

• The best example is in HIV/AIDS. Indeed, the so called anti-retroviral treatments are the mainstay of AIDS management (there is no vaccine for this infection) and have dramatically improved the outcome
• Actually, there are around 24 drugs that stop the HIV virus multiplying
• There need to be so many as patients get resistant to individual drugs and combinations of different agents work better than single drugs

• You may remember during the Swine Flu H1N1 epidemic there was much enthusiasm for the antiviral drugs Tamiflu and Relenza that we’re widely prescribed in primary care
  • In truth the infection turned out to be not as serious as was feared
  • The only difference was a modest reduction in the number of days people felt ill for and indeed recent analyses have suggested they weren’t that effective 
• This all suggests that antiviral drugs make sense as a concept but there was no evidence that drugs which worked for one virus would necessarily work for other viruses

What about using existing antiviral drugs for Covid-19?

• Lots of have been tried!
• There are a vast number of trials investigating a whole range of existing antiviral drugs for Covid-19
• I searched the available databases yesterday and found this!

• The only drug thus far with any positive data is remdesivir
  • There was initial enthusiasm for this drug as a specific antiviral agent for Covid-19 19
  • It had been developed for use against other corona viruses eg  SARS
  • Some data suggested it could make a modest difference to how long people had symptoms 
  • The USA was very enthusiastic and, looking after their own interests, went out shopping!
  • Although there have been many trials, the most recent data suggest the benefit from remdesivir is minor and it is not a candidate for widespread use

How easy will it be to develop a new drug from scratch?

It is simplest to divide up the process into stages:

• The early laboratory work for identifying a possible drug
• Testing the drug in animals
• Testing the drug in humans

• There is a considerable drop out at each stage (one estimate is that only 0.5-1% of all drugs  tested in animals end up being marketed for human use)
• The full process takes on average 10-15 years
• What it costs is obviously variable, but a reasonable average for recently licensed  drugs is between $1-2bn
• Developing drugs is a risky business!

What are the risks?

There are clinical and commercial risks.  I have put these in a reasonably sensible order, but for example evidence of harm can emerge at any stage, which would at that point stop the drug being developed further or sold

• Drug doesn’t work
• Drug works but proves to be harmful
• Early investors lose confidence and development stops
• Drug works but gets overtaken by better/cheaper drugs
• Technical problems in production etc
• Disease stops being a problem so sales plummet

Who takes the risk?

• Conventionally this has been the big pharmaceutical companies
• However much more common these days is for ‘big pharma’ to enter into the process some way down the line and pay a reasonable premium for a license to develop a drug further 
  • After university researchers have shown there may be a promising future for something they have discovered
  • When a small biotech company, perhaps set up by a university specifically to further develop their discovery, has shown benefit in animal testing
• To get to the stage, individual researchers, universities and small companies may seek external speculative investors or use their own funds (including researchers remortgaging their own homes!)

Should this not be different for a global pandemic like Covid-19? 

• It has been easy getting billions for vaccine development 
• By contrast, governments and other organisations have only funded $millions (not billions) into research for new drug treatments
• There has to be some shared risk/reward for companies to make the size of investment that is needed

Is there any possibility of speeding up/making the development process cheaper and quicker ?

• Again, the short answer is that the pace of change in drug development is staggering
• Use of artificial intelligence (* see my post on protein structures) has meant that the very lengthy development stages can be reduced in time and screen thousands of potential drugs very quickly so that clinical development can focus on the most likely 
• The clinical testing period which has up to now been say 5-10 years can also be reduced as has been demonstrated by the speed at which vaccines have been brought to market
• There is one major difference between vaccines and other drugs in that the mechanism of vaccines – to enhance the body’s production of its own antibodies – is generally known to be successful and safe
• For drugs designed for new treatment, this is more speculative

*https://makingsenseofcovid19withs.com/2020/12/08/is-this-the-greatest-breakthrough-in-medical-science-for-a-generation

Conclusion

• It would have been great to have reached the end of this difficult year with exciting news of a successful new antiviral drug to match the success of vaccines
• Of course, if the vaccines are successful and provide long term protection, then new treatments may not be needed
• However, we should be reassured that such development is happening (albeit more slowly) but also could make us better able to cope with the next viral pandemic

And finally!

This will be my last post this year.  Thanks for all the positive comments and the interest across so may countries.  Hopefully our governments will be better able or willing to ‘follow the science’ in 2021!

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Covid-19 would be less of a worry if there was a very effective treatment

It is an obvious fact that the world might not worry about the dangers of catching Covid-19 if there was an effective and safe (and hopefully cheap) drug to stop the disease ‘in its tracks’. The idea is that it could be taken when people  had the very first minor symptoms of being unwell or even when testing positive.  As a  historical parallel, in the pre-antibiotic era, infections that we now consider minor such as ear infections and sore throats could have led to life threatening complications.  The population now, though, no longer worries about such disorders because antibiotics are so effective (although the major concern of antibiotic resistance is real).  This post thus addresses how likely is it that we could get such antiviral drugs that could be similarly effective and appropriate for widespread use in Covid-19.

Comparison with antibiotics The comparison with antibiotics and bacterial infections is interesting.  In most countries those who visit their general practitioner with a  sore throat or a chest infection these days would be denied antibiotics:  the advice being that (without testing)  the illness (a) is due to ‘a virus’ and hence  does not respond to antibiotics and (b) will settle down on its own.  Thus, we have developed an acceptance  that common viral infections do not  need specific treatment and are not likely to become serious.  Covid-19 has proved the latter to be untrue, so where are we on the path to addressing the former? 

When might drugs be used in Covid-19? Drugs might be used at 3 stages

• To stop people becoming infected after being exposed to the virus 
• To stop the virus actively producing many copies of itself in the body and prevent severe clinical problems
• To treat the ongoing clinical problems, and especially the complications, caused by the virus

Vaccines cover the first stage. Drugs for the third stage cover the range of drugs from simple agents that control symptoms such as paracetamol, to those used to treat and control the serious consequences and the complications of infections.  (Drugs in this class include dexamethasone that received much publicity recently as it reduced the number of deaths in Covid-19 patients admitted to intensive care units.)  

What is lacking are drugs that stop the virus, once it has established itself, from causing further harm.  Viruses work by entering our cells and then taking them over and using them to produce millions of copies of themselves.    If that process can be stopped, then if someone became infected the virus would be unable to cause much harm.  Such drugs are known as antiviral agents.

Are antiviral agents effective in other viral infections? Although many viral infections lack an effective drug to stop the virus multiplying, there are  also a large number of infections where antiviral drugs are useful.  These  drug names often end in ‘vir’.  Most widely known is acicolovir/acyclovir (trade name Zovirax), which can even be bought ‘over the counter’ for the treatment of cold sores and shingles. There are also a number of antiviral drugs that work in influenza.  These include drugs such as oseltamivir (known as Tamiflu) and zanamivir (known as Relenza).  Indeed, in the previous epidemics of bird flu and swine flu, governments spent millions stockpiling these drugs.  They were of variable benefit and in fact were never widely used. There are also now at least 20 antiviral agents that have been used to stop viral multiplication in HIV/AIDS.

Does each virus need its own antiviral drug? Antibiotics, such as  penicillin, are typically active against many different bacteria.  The range of bacteria covered by one antibiotic can vary. Some antibiotics are ‘narrow spectrum’ and active against a few bacteria , whereas some are ‘broad spectrum’ and active against a larger range.  By contrast there are very few antiviral drugs that are considered broad spectrum (apart from remdesivir, see below) and most are very specific.  Indeed, the large number of drugs used to treat the AIDS virus attack very different aspects of the virus’s activity (and indeed are used in combination).

Where to start looking for antiviral drug against Covid-19? One major hope was that there might be no need to develop a new antiviral drug, as that would take too long, but that drugs of known benefit in other viral illnesses could be also used for Covid-19.  Covid-19 is one of a family of so called RNA viruses which include those that caused the epidemics with SARS in 2002 and the MERS (Middle Eastern Respiratory Syndrome) in 2012.  It is also related to the Ebola virus which caused such concerns in Western Africa in 2014-16. 

Remdesivir is one of the few broad spectrum antiviral agents and has the potential to block the pathway by which RNA viruses multiply.  It was originally hoped it would be useful to combat the Ebola and MERS pandemics.  In practice, in clinical trials, remdesivir did not prove useful in treating Ebola but the drug was still a strong candidate to try in Covid-19. 

There have been at least 10 trials and there are now a number of studies suggesting that this drug can be useful in severe Covid-19.  The most widely published study showed that in patients who developed severe lung complications, remdesivir reduced the length of time  a patient was in hospital from an average of 15 to an average of 11 days.  Around 20% had serious side effects.  Thus, whilst useful it is not a miracle cure and the safety profile means that it is not suitable for widespread use in  people with mild disease.

Are there any new antiviral drugs on the horizon that can treat people with early Covid-19 to prevent serious complications?

As implied above most of the work has been done on reusing (or ‘repurposing’ in the jargon) existing drugs, and there is no obvious candidate.  To develop a drug from scratch that is directed towards Covid-19 will take some time.  The approach is first to study how the  virus divides and attacks human cells.  This information is then used to design drugs to block such actions.  This can be very complex work but in June research from California has achieved in 3 months what in normal times can take two years.  The research has identified the key mechanism that the virus uses to multiply in human cells and is now starting to design drugs to address this.  They will have to be tested carefully of course for safety and benefit.  Even with success at every stage, having a new drug available for widespread use must be a couple of years away.

Does resistance occur with antiviral drugs?

Like everything else the answer is ‘it varies’!  It depends on whether the virus mutates in such a way that is still causes illness but escapes the process by which the drug works.  The cold sore virus has not become resistant to acicolovir as far as I am aware, despite the drug being so widely available.  By contrast the problem for patients with HIV/AIDS is that the development of new antiviral agents barely keeps up with the development of resistance to existing agents. It is too early to know for sure whether Covid-19 virus will develop resistance to remdesivir but a study at the end of June, from India and Japan, suggests that the virus could mutate to become resistant to remdesivir.

One problem with Covid-19 is the long incubation period

The incubation period for seasonal flu is probably about two days.  Indeed, the studies with Tamiflu showed that one needed to take it within a day of symptoms appearing to have the desired effect.  Covid-19 has a longer incubation period of maybe 5-7 days and by the time that symptoms are present, the virus has already multiplied and it is perhaps too late for any antiviral drug to work.  However, recent research from Belgium using computer simulations has shown that with a robust ‘track and trace’ system which can identify individuals and their contacts with the virus, the use of antiviral drugs even before any symptoms appear can make a big difference in helping control local outbreaks

Conclusions:

• There are no existing drugs that are useful in treating people with Covid-19 to prevent the infection becoming serious.
• It should be possible to develop new drugs to stop the virus multiplying  in the body’s cells and prevent the serious complications
• This will take time to develop and especially to prove the drugs are safe and do not cause more health problems than they prevent
• Being optimistic, strategies that combine successful contact tracing and testing with early use of any such treatments could be an alternative to a vaccine if the latter proves too difficult to achieve