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Thor’s hammer

6/11/2021

 
“Hello Dad, how are you today?” asked Thor, the God of Thunder.
 
“To be honest son, I’m a bit under the weather really. I’ve managed to catch Covid-19 from Hela, your sister, and I’ve just called to let you know you’re a contact and need to test and self-isolate” said Odin.
 
“It’s okay father, I don’t need to worry. I will smite this dastardly virus with my mighty hammer, Mjolnir. No virus is going to get the God of Thunder so easily”
Molnupiravir
Microbiologists in fancy dress? Smite that virus!
Okay, it may not have gone exactly like that, but I’m sure I saw something on the BBC 10 o’clock news a couple of nights ago saying something to do with Mjolnir.
 
Oh, I know what it was! It was a new treatment for Covid-19; a drug called Molnupiravir …it was apparently named after “Mjolnir”, the Norse God Thor’s hammer, as it was expected to be able to knock down viruses like the God of Thunder.
 
What is Molnupiravir?
Molnupiravir was originally developed as an anti-influenza drug as this was probably where it was expected to have its most beneficial effect both for severe seasonal influenza but also if an influenza pandemic occurred (as well as a return on investment!). When Covid-19 went global lots of pharmaceutical companies started looking again at their various experimental antivirals.
 
Molnupiravir, also known by the trade name “Lagevrio”, is a prodrug that works by causing errors in viral RNA replication; it effectively messes up the genetic code of the virus as the virus is trying to reproduce. It is therefore expected to be most effective if it is taken to prevent virus being created in infected cells so that it can stop an infection from becoming established.
 
How does Molnupiravir work?
Molnupiravir is metabolised by the infected person to produce a molecule that looks like the nucleosides cytidine or uridine which the RNA polymerase then uses instead of normal cytidine or uridine when trying to build chains of RNA. This “fake” cytidine or uridine then causes multiple errors in the chain of RNA, eventually causing so many errors that the virus cannot cope. This process is known as “viral error catastrophe” or “lethal mutagenesis”.
 
The thing that makes Molnupiravir really exciting is that it is oral. The previous antiviral treatment Remdesivir is intravenous and so can only be given in a healthcare setting, whereas an oral drug can be given in the community at the earliest opportunity available (if you can actually get to see your GP in time!).
 
What is the evidence for the use of Molnupiravir in Covid-19?
In the clinical trial conducted by the pharmaceutical company Merck Sharp and Dohme (MSD), Molnupiravir was said to reduce admission to hospital by 50% in high-risk patients. The study was stopped early because of these beneficial effects and the feeling that to continue to give a placebo to the control group was no longer ethical.
 
OK, so last Thursday (also known as Thor’s day! Weird coincidence!!) the Medicines and Healthcare products Regulatory Agency (MHRA) approved it for use in the UK and the UK Government has pre-ordered 480,000 doses at a cost of £25 million. So let’s look at the evidence. What did the journal article really say?
 
Errrrrrrr, what journal article? Where is the peer-reviewed journal article showing how the research was conducted, what the patient group make up was like and what did the results show?
 
You’ve guessed it, we’re back to science by press release again! YOU HAVE GOT TO BE KIDDING ME!!!!!!!
 
Okay, deep breath. What did MSD say in their press release?
 
MSD have reported that “Molnupiravir reduced the risk of admission to hospital or death by around 50% in non-hospitalised adults who had mild to moderate Covid-19 and were at risk of poor outcomes”. Apparently 7.3% of the Molnupiravir group (28 of 385 patients) and 14.1% of the placebo control group (53 of 377 patients) were either admitted to hospital or had died by day 29. In fact, there were no deaths in the Molnupiravir group compared to 8 deaths in the placebo group. Adverse events were the same in both groups, 12% versus 11%.
 
This looks great! 50% reduction in hospitalisation or mortality BUT where is the full data? I know pharmaceutical companies want to get their drugs to market asap, especially when there are suggestions that the rate of severe Covid-19 is already dropping and if they wait to long their will be no market left for them, but surely the scientific community and the public should be able to scrutinise the data fully.
 
What do we need to know?
  • How was Covid-19 diagnosed in the study?
  • What criteria were used to decide if the Covid-19 was mild or moderate (especially since some died!)?
  • What criteria were used to decide if the person was at risk of poor outcome?
  • Did the two groups receive the same care otherwise e.g. steroids, IL-6 blocking agents, ventilatory support, time to treatment, etc.?
  • Where the two groups, Molnupiravir and placebo, the same in terms of demographics and risk factors?
  • What was the spread between the two groups in terms of variants of SARS CoV2?
  • What were the statistical analysis results? As the groups are so small could the difference in results have occurred by chance?
  • Do we think that a group of 385 people is large enough to say the drug is safe?
  • Have there been any other studies using Molnupiravir for influenza that show safety?
 
Gosh am I really greedy in wanting to know more about this than just the “Good News” headline? These are the kinds of questions that scientific studies should answer, and in my opinion pharmaceutical companies should publish results as soon as they are available. I don’t buy the argument that it takes too long to publish anything. If they refuse to use the standardised independent journal peer review method, why can’t a pharmaceutical company not just use their own website as the publication platform to put out all the data for others to scrutinise? All of this cloak and dagger stuff just makes cynics like me suspicious and gives fuel to the conspiracy theorists. Stop it!
 
What do the UK Government and the UK medicines regulator say?
The UK Health and Social Care Secretary Sajid Javid has said “Today is a historic day for our country, as the UK is now the first country in the world to approve an antiviral that can be taken at home for COVID-19. This will be a gamechanger for the most vulnerable and the immunosuppressed, who will soon be able to receive the ground-breaking treatment.”
 
This makes me uncomfortable as it sounds like boasting that we did it faster than anyone else. “Historic, game-changer and ground breaking” have seriously been over used by politicians who then U-turn or hide the truth…Nightingale Hospitals, PPE procurement and lateral flow tests to name a few game-changers! Does that mean there might have been short cuts along the way? What did the Medicines and Healthcare products Regulatory Agency say? Remember that the MHRA is part of the Department of Health and is mainly funded by the pharmaceutical industry itself.
 
Dr June Raine, MHRA Chief Executive, said “following a rigorous review of the data by our expert scientists and clinicians, we are satisfied that Lagevrio (molnupiravir) is safe and effective for those at risk of developing severe COVID-19 disease and have granted its approval …With no compromises on quality, safety and effectiveness, the public can trust that the MHRA has conducted a robust and thorough assessment of the data.”
 
At least this is less sensational but I wish they released their analysis of the data! I hope they’re right, but I am worried that a single small study where a drug was given to only 385 people really justifies the statement “no compromises on quality, safety and effectiveness”. I would much prefer to see the data myself.
 
But let’s face it, it doesn’t matter what I want, Molnupiravir has now been authorised “for use in people who have mild to moderate COVID-19 and at least one risk factor for developing severe illness. Such risk factors include obesity, older age (>60 years), diabetes mellitus, or heart disease”. The drug should be started within 5 days of the onset of symptoms and is taken twice a day for 5 days. The cost; £520 per course.
 
So where do I get my Molnupiravir?
Whoa there! Hold you horses? The UK Government, the MHRA and even the BBC News have all said we can have Molnupiravir BUT when you get to the bottom of the Department of Health’s web page you find this statement right at the end “the Government and the NHS will confirm how this COVID-19 treatment will be deployed to patients in due course”. So no you can’t have it yet!
 
So, after all that excitement, all the trumpet blowing and news headlines, Molnupiravir isn’t actually available yet. MSD have said they will try and produce 10 million doses by the end of the year, and a further 20 million doses next year, but in reality, that is just a drop in the ocean and I think it is very unlikely that, on this scale, this is going to be the “game-changer” or “ground-breaking treatment” that the Health Secretary says it’s going to be. Although at 30 million doses MSD will make about £1.5 billion out of a defunct flu drug!
 
Oh well. We can’t just get exposed to SARS CoV2, take a pill and everything will be alright just yet. So it’s back to the hand washing, face masks and physical distancing then!
 
Is this the only message Microbiologists can come up with…”BLAH, BLAH, BLAH” to quote Greta Thunberg.
 
OMG!!! Having just written this blog it seems that Pfizer want to steal some of MSDs limelight as just a day after the MSD press release they have announced the results of their own oral anti-Covid-19 drug, Paxlovid, in yes you’ve guessed it, a press release. Yet again the trial was stopped early due to “fantastic results”, and yet again the numbers are small (1,219 patients divided between treatment and placebo) but as we have come to “expect” from Pfizer “their drug is better than your drug” apparently reducing admission or death by 90%.
 
Oh dear, the game of pharmaceutical press release one-upmanship goes on….
Paul F
17/12/2021 09:41:37 am

Still love these. I do miss talking to you about bugs and drugs. I'm going to ask everyones favourite microbiologist his thoughts on Sotrovimab, having got mildly excited myself.

Always grateful for the education. And hope you have an excellent Christmas time.


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