Thread by @SGriffin_Lab

This is a really important paper. Some have said it's a bad news story...
The question is should £1bn have been spent on this drug in 2021 following just a prelim analysis of a much smaller trial...
However, before we start, bravo @ChrisColButler & team👏
papers.ssrn.com/sol3/papers.cf…

First, a little on molnupiravir (Lagevrio).
This is a nucleoside drug, or "nuc", originally named EIDD-2801 by scientists at Emory University. It was named Molnupiravir after Thor's hammer, Mjölnir.
Nucs are the building blocks of genetic material, so RNA or DNA. Nucs are a well

established class of agents used against RNA viruses as they target a unique feature of these viruses - the RNA dependent RNA polymerase, an enzyme that makes more RNA using RNA as a template. We don't have these in mammalian cells, so the idea is you can target this selectively

...which is true, to a point, as with all drugs!
So, most nuc drugs look like a normal building block, but they've been modified - most of the time they become part of the growing RNA chain and can't have another block added, these are "chain terminators". But, Molnupiravir is a

bit different. Instead of halting the chain, it becomes part of it and waits until the next time the RdRP comes along, using the RNA with the Molnupiravir nucleotide within its sequence. When this happens, the RdRP gets confused and can read Molnupiravir as one of two different

nucs, or bases. This means that mistakes are made, and as more Molnupiravir enters the RNA these errors multiply until the genetic code of the virus starts to read like gobbledegook, no longer making sense to the other parts of the RNA, or indeed the ribosomes that make proteins.

This results in something called "error catastrophe", which basically means the virus is messed up beyond repair...this happens for some other nucs, such as Favipiravir (a flu drug in Japan) and Ribavirin. The issue with this is that sometimes the cell can use the drug molecule

to make DNA, rather than RNA building blocks...and if this happens there's a chance your DNA can become mutated...now, before this starts a tirade of trolls talking 💩, this generally only happens at much higher concentrations of drug, but we ensure this and other "teratogens"

aren't given to kids or pregnant mothers.
Right, is it any good? Well, YES! Surprisingly enough it's one of the few really good nucs against SARS-CoV2 because, like remdesivir, it can slip past the virus' quality control system, an enzyme called NSP14, and so it's really potent

in virus culture and, if given early, in animal models vs SARS1, 2 and MERS. It doesn't really have any bad toxicity issues, so this was a perfectly good reason to start trialling it in people, especially as, well, you know, there is a deadly coronavirus pandemic causing issues!

So, this brings us to the trials...and why this drug, unlike things like Paxlovid, Remdesivir etc is only approved in certain countries.
First, there were lots of discussions around the teratogen issue. No signal yet that this is a problem, but time will tell.
Second, the first

trial run by Merck and partners on this drug, given early during infection, was initially reported as a preliminary analysis, i.e. before all the data had been analysed. It looked good enough, and importantly it was used in high risk patients, mainly unvaccinated, and it gave a

significant reduction in the risk of hospitalisation or death, around 50%. Now, compare to early dose remdesivir or nirmatrelvir (the active part of paxlovid), and these were in the 90%+...
But, Molnupiravir was around before paxlovid and it was given orally, unlike remdesivir

infusions, so maybe the application would compensate. It was only after the UK ordered a huge number of doses that the full analysis revised the figure down for Molnupiravir...to ~30%!
The EMA and FDA still haven't approved it, but other countries have, and studies have shown

real world benefit, albeit observational rather than placebo-controlled...
So, on to #Panoramic...and what it means for the UK government investment...
Well, the headline is that Molnupiravir did nothing to reduce the risk of hospitalisations vs placebo. A bad thing...however...

Panoramic was a BIG study, over 12K people in each group. The population was actually rather different to the original trials - rather than being unvaccinated and at very high risk, patients were either >50 or 18-49 with a comorbidity. Now, this isn't low risk by any means, but

it IS different, which we can see from the fact that only ~100 people in either group ended up in hospital, less than 1%...#VaccinesWork
Also, the trial period was just after the 2021 booster campaign, into 22, and the virus was BA.1/2 omicron, which we know carries lower risk of

serious problems in recently vaccinated adults, measured case by case (actual clinical impact needs to be factored by prevalence, but the populations here are fixed and all infected). So, there's a question whether even 12K patients in each arm is enough to discern differences in

risk...but there's a limit to what can be done!
Interestingly, the recovery of patients that didn't enter hospital was sped up by Molnupiravir, and the virus load decreased more rapidly...i.e. the drug DID work to reduce SARS2 replication, so why did this not translate to halting

hospitalisations? This is obviously difficult to say from this trial, but we need to remember that severe COVID is as much an immunological disease as it is virus-driven, all the more so as time passes. More good news, was that very few side effects were seen for the drug, so it

WAS the case that people were recovering more quickly (although it's hard to define "recovery" the same way in everyone).
So, why am I warbling on about this? Well, there has obviously been a lot of negative interpretation of this, and this is all the more relevant when you think

about the way this investment was made, and how it was announced, particularly in comparison to some other medicine decisions we've seen recently.
On the back of what turned out as mediocre initial efficacy, Sajid Javid and the PM called this a "game changer" that would protect

vulnerable people as we "live with COVID"...so, on the face of it, a good thing that we're investing to protect those most in need...the only issue is that it looks as though had Molnupiravir been the only option, the majority of vulnerable people would NOT have been protected.

In this interesting @bmj_latest article, it's mentioned that just a fraction (~1%) of the >2M doses of Molnupiravir bought by the UK have been used...and it's not clear how this might be rectified before they expire...I appreciate that this was several PMs ago🤪, but the economy

wasn't exactly flush.
So, what's my point? Merely to highlight the difference in attitudes for Molnupiravir when "living with" was being pushed, to now, as #CEV face winter and are being asked to PAY for prophylaxis that could give their lives back. A bloody disgrace.
#Evusheld

Oops, realised I forgot the link to the @bmj_latest article - bmj.com/content/379/bm…
@cv_cev @cathy_finnis @drlennardlee @sheencr @BinitaKane