Another game changer – or not? 

Could a 5 day course of pills from your local pharmacist make Covid-19 a minor illness?

In the past month, the  drug companies Merck and Pfizer have both issued a press release about a new anti-Covid-19 pill.  These suggested that for newly diagnosed patients with Covid-19, a short course of these pills can substantially reduce – and in the case of the Pfizer pill almost take away  – the risk of needing to be admitted to hospital.  How justified are these claims and can they take the ‘sting out of the tail’ of this pandemic?

(Note to readers: as there is more detail in this post than some of you want, to make it easier you can skip the sections in italics!)

Tamiflu and the 2009 Swine Flu pandemic

• Lest you feel this is the stuff of science fiction there is the example of Tamiflu and the swine flu epidemic in 2009.
• Tamiflu a pill that could be taken at first symptoms of the H1N1 virus (behind swine flu)
• At the time this epidemic caused a similar level of public anxiety as CoVid-19
• Potentially it was suggested Tamiflu could prevent hundred of thousands of deaths in the UK alone
• It was developed to be a drug which potentially could be obtained without a prescription to enable rapid take-up during such a large-scale epidemic 

 

• Encouraged by scare stories in the media, the UK government stockpiled £500 million of the drug, subsequently to find that that by the time it was administered  it had very little clinical benefit in terms of reducing recovery time
• And that money spent was probably wasted 

What about Covid-19?

• In this blog in July 2020, I stated the obvious (so you don’t need to be impressed!) 

• A successful anti-viral drug could stop the virus producing many copies of itself and hence stop people who had contracted the infection becoming unwell in any meaningful way
• This is what antibiotics do to combat infections caused by bacteria;  but unlike antibiotics which work against many different bacteria, each virus needs is own antivirus drug
• There was not a specific anti-Covid-19 drug, so early on in the pandemic doctors tried many anti-viral drugs which had been successful against other viral infections such as HIV
• The most promising drug was remdesivir, which had been partially successful against other coronaviruses such as SARS, however in clinical trials the impact on Covid-19 was only modest
• Remdesivir also needs to be given by injection into a vein.  What was needed, and should be possible, was a drug in pill form and easily obtained from your local pharmacist
• The ‘game changer’ could be that once infection had been diagnosed, say by a lateral flow test, the patient could buy a short course of the pills from their pharmacist
• We now have two pills that can be potentially taken in this way

The Merck pill: Molnupiravir

• This is not a new drug but had been shown to work against lots of other viruses, especially coronaviruses
• The US Biotech Company ‘Ridgeback Therapeutics’ found the drug stopped the Covid-19 virus producing sufficient copies of itself, when tested in ferrets
• Merck then thought to test this in humans
• It seems to work in quite a clever way: basically the copies of the Covid-19 virus produced when exposed to Molnupiravir are so changed that the virus can’t further reproduce

What are the new clinical data from Molnupiravir?

• The data have only been presented in the company’s press release and not in a scientific publication (this is the new normal in this pandemic!)

• The pill was tested on the following patients:
  • Adults aged 18 and over
  • ‘mild to moderate’ Covid-19 for less than 5 days
  • Had one feature that made them at risk of developing severe illness
• The trial in the press release compared 5 days of 2 capsules a day with a placebo
• The trial had originally planned to continue to May 2022, but an early analysis of the results showed that Molnupiravir was clearly effective – so the trial stopped recruitment
• By 28 days after the start of treatment, 7% of patients on molnupiravir needed to be hospitalised, compared to 14% on placebo
• More impressive still,  there were 8 (2%) deaths in the placebo group and none in the Molnupiravir group
• There was no increase in the number of side effects between the 2 groups
• The data have been scrutinised by drug regulators in the USA, UK and Europe.  In the UK, the  MHRA were sufficiently impressed to have approved the use of the drug
• Consequently the UK government has bought 500,000 doses 

The Pfizer drug: Paxlovid

• This is not a single drug but a combination of 2 drugs
  • The first is an antiviral drug that specifically targets Covid-19
  • The second is the well-known anti-HIV drug: Ritonavir, which works by slowing down the body’s mechanism to break down the antiviral – this keeps the circulating  level of active antiviral higher (clever I think!)

What are the clinical data from Paxlovid?

• Again the data have only been presented in the company’s press release and not in a scientific publication
• The trial was a bit like Merck’s trial and compared 390 patients who were at ‘high risk’ of getting serious illness to a similar number who were given placebo
• Again 5 days of two capsules a day were used
• The results were even more impressive:
  • Less than 1% of Paxlovid patients needed hospitalisation compared to 7% on placebo. 
  • There were no deaths in the Paxlovid group and 7 in the placebo group
• The drug regulator in the USA, the FDA, on the basis of these results, advised stopping the trial as the data were overwhelming.  The FDA are likely to give emergency use authorization very soon

But there are an important number of unknowns about both these drugs

1. Which group of patents would benefit from these drugs? Conversely which groups would not benefit: ie including both
   1. those who would not need the drugs as they would not be at risk of developing serious problems?
   2. those for whom these drugs would be given too late and other treatments should not be delayed?
2. Most importantly until we have seen all the data, it is not clear who these groups are
3. Indeed, studies by Merck suggest that their drug is not useful once the infection is severe – that is perhaps not unreasonable though, if it is given past the time the virus has done its damage
4. Also, although the patients in the Merck trial had to have “1 characteristic or underlying medical condition associated with an increased risk of severe illness from COVID-19” until the data are published we don’t know whether these patients were typical of patients with mild Covid-19 
5. How is mild or moderate disease defined and what criteria were used to conclude someone is at risk?
6. For example in the Merck trial the 14% risk of hospitalisation and 2% death rate in the placebo group are much higher than the current situation in newly diagnosed patients in USA/UK/Europe

b) What about side effects?

• Reassuringly the total number of adverse events was low for both the Pfizer and the Merck drugs
• We haven’t seen the details of the side effects in these trials, just the total number of side effects combined
  • The trials were too small to know whether there are any individual major side effects we should worry about
  • If either drug was going to be used very widely we would need this information
• BUT: this is all normal process in drug licensing, and at this stage in drug development we won’t have all these answers, but emphasises the need for longer term studies on patients treated with these drugs as they become licensed 

c) Could Covid-19 become resistant to these agents?

• Theoretically the answer must be yes
• Molnupiravir  works by disrupting the DNA of the virus, it is possible that whilst this could encourage the development of mutations that are less dangerous, equally these mutations could strengthen the virus –  but that seems unlikely 
• Resistance is also possible against the Pfizer drug: the history of anti-HIV therapy is sadly associated with the development of drug-resistant strains
• Although such resistance is possible, the duration of treatment is quite short which is helpful
• On the plus side, because these drugs do not target the spike protein, which has been the main source of new variants, eg Delta, drug resistance is less likely.  Indeed these drugs could be very useful if other new, and  potentially vaccine-resistant, variants become widespread

Drugs versus vaccines

• This to me is an interesting question especially as, in practice, the real benefit of vaccines has been to protect against severe infection rather than against contracting the infection
• Indeed, the vaccine data suggest they can give about 90% protection against being hospitalised – ie the same benefit as claimed from the new Pfizer drug (and higher than the Merck drug)
• Neither of the companies’ press releases specify if the patients in these trials had been double vaccinated
• Thus a key question is whether these drugs offer any additional protection over the vaccines
• Although a reasonable answer is that
  • These drugs act in a different way and can add a second line of defence for people who get sick despite being vaccinated
  • Given waning immunity, these drugs may be particularly useful in people for example who have not had a booster or for whom the immune response from the course of the vaccine is weak 

Conclusion

• Yet again the media and pharmaceutical industry  are talking about ‘game changers’ in our fight against Covid-19 
• I do acknowledge that these drugs, given to the right people at the right time in their infection, could provide major protection against severe illness – we just don’t know who these people are
• More data are needed on both short and long term side effects

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