David Grainger
@sciencescanner
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Biotech entrepreneur & Partner @Medicxi Advocate of virtual, asset-centric R&D. All opinions my own
Cambridge, UK
Joined September 2009
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I do sense
@borisjohnson
@MattHancock
are in danger of getting it wrong tomorrow. Now over-80s are vaccinated in UK we have to release essentially all
#lockdown
restrictions
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HCQ is dead then. Blinding is needed to prevent biases creating a false-positive signal. For a negative study open-label random is just as powerful as double-blind...
#COVID19
Here comes another dataset of
#Hydroxychloroquine
from an open-label randomized controlled trial in China
No difference in 28-day
#coronavirus
negative conversion rate for HCQ + SOC vs SOC
No difference in 28-day symptoms alleviation rate either
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Lesson of the day: nothing in drug R&D is ever de-risked
If you want to build a PharmaCo (rather than a hedge fund leveraging binary read-outs) you have to focus on resilience to bad outcomes - NOT maximising yield from good ones
We don’t see that mentality in biotech enough
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@IsabelOakeshott
@brexitparty_uk
I agree. A deal with
@brexitparty_uk
is the only way
@BorisJohnson
can go to the polls with confidence
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@JimBethell
Perhaps I could respectfully point out that in outer London, wood burners create more PM2.5 than vehicle emissions
ULEZ is a political choice not a health necessity
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Seems obvious we should make this adjustment
@grantshapps
And increase the enforcement at the same time.
Make easier to comply & more painful not to - because a minority who fail can cause a lot of harm
I mean this as a genuine question
@grantshapps
.
Surely people quarantining could be allowed out for 30 mins a day? No shops, pubs just for a socially distanced walk? Dogs would appreciate it!
For those following the rules, especially with no gardens, it feels so heavy-handed.
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Suddenly it’s personal. Steve was one of my scientific heroes and a great mentor early in my career. I remember fondly his kindness when I found myself in Seattle - invited to share his family’s Passover feast. Truly one of a kind. RIP
We have lost Dr. Steven Schwartz to Covid19. Many know Steve as
@UW
professor of Pathology and director of the Cardiovascular Pathology Training Grant. It’s a sad day
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WARNING: PCR is INCREDIBLY sensitive. I do wish people would stop looking for
#COVID19
RNA in any sample they can lay their hands on....
This is not useful information.
#COVID19
RNA is everywhere. The question is: where are the infectious particles?
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This is a bad decision
The US has gone from the random stupidity of Trump to the calculated stupidity of Biden
These extraordinary times and circumstances of call for extraordinary measures.
The US supports the waiver of IP protections on COVID-19 vaccines to help end the pandemic and we’ll actively participate in
@WTO
negotiations to make that happen.
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Actually guys - dont bother. Just enjoy your BBQ and remember that such easily modifiable risk factors are noise compared to your genetic risk. You will die - the only question is how much of the good life you can pack in before you do…
Before you fire up the grill today, watch this STAT explainer on how to lower your
#cancer
risk at the grill.
#HappyFourthOfJuly
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@RoyalFamily
@Madz_Grant
Sad to learn of the death of HRH Prince Philip, Duke of Edinburgh, this morning
He was a wonderful man, who in his role as Patron of
@TheBHF
I was fortunate enough to meet. His genuine engagement and passion for life was inspirational
We may not see his like again
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Remember this is happening next time you suggest that mask-wearing is still needed “to reduce the risk of new variants”
It is, and since vaccines were available, always has been performative nonsense
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Its absolutely right that Vinay goes to town to debunk the mask myths
We need to make this battle the poster-child for evidence-led public health advice
Far too much of what we were told to do during
#covid
lacks any evidence base whatsoever
Excuses for why masking FAILED in the Cochrane Review
Do we really demand confidence intervals exclude all meaningful benefits before we throw out medical practices?
I investigate
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I got the $AZN vaccine first dose this morning - and it’s actually quite an emotional experience. It feels like a concrete step towards normality - but also for someone who has spent a career in medical research a vindication, even celebration, of the work of so many great people
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Its easy to look at the Italian death rates (950 in the last 24hrs) and think “the lockdown is not working”.
But it is. The daily death toll (which is a 28 day lagging indicator) has been essentially flat for a week
That is curve-flattening - and exactly why we must
#StayHome
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Glad to hear someone calling out the madness of vaccinating the planet twice a year
The booster obsession is because we are trying to halt transmission with a vaccine that does not rsally do that…
1/n
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Vinay gets it right again
Politics & drug regulation are a dangerous mix - but a common cocktail in 2022
Sensible people know approving vaccines for millions who mostly just had omicron based on mouse data is a. not a good idea & b. not acceptable for a company making billions
Peter Marks continues to err. Gruber/ Krause would not have. FDA too political
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Before we start a debate on whether 94% is better than 90% let’s remember you’d need a head-to-head design to answer that - and a simply ginormous study size to show stat sig superiority
$MRNA and $PFE efficacy are indistinguishable
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This is interesting (to me at least) because it’s an effect we predicted almost 20 years ago now
Following thread explains exactly why this is what you’d expect
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(H/T
@manal_mehta
)
A = Higher Risk. O = Lower Risk Potential relationship between the ABO Blood Group and the COVID-19 Susceptibility (From 3 Wuhan hospitals)
#COVID19
#coronavirus
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@emilyhewertson
Never. Socialism is a flawed concept - so they would have to abandon their founding principle which seems impossible
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After mininterpreting data on the need for a booster, we are now seeing data like this misinterpreted as a need for boosters
Its always going to be true that you have more efficacy for a month or two after a booster while neutralising Abs are high - but its the wrong comparison
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Watching the fall-out from the $AZN/Oxford
#covid
vaccine data this morning (including the initial drop in $AZN share price) is an object lesson in interpreting clinical data
(1) The headline 70% efficacy may be misleading (2 regimens, one of which is ~90% effective)
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If anyone who follows me is doubtling whether they should get the $AZN/Oxford vaccine when its offered to them, perhaps worried by the questions over efficacy… DO NOT HESITATE!
The risk of not being vaccinated is FAR higher
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Ok. If you only read one thing about
#coronavirus
make it this:
If you doubt whether you need to act now, or think some people are over-reacting read this (
@FrederickFredr3
I’d be interested what you think having read it)
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Its interesting that the people now calling for or considering a patent waiver for
#covid
vaccines were completely silent this time last year when companies were investing billins and working like crazy to discover and develop those precious vaccines
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Its obviously impractical to boost everyone every 6 months to keep neutralising Ab titres high (and so have maximal protection against harmless transmission)
So what we are seeing happen is well short of Evidence-Based Medicine
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So Im a bit late to the party with by big news for the day… been too busy actually doing the job!
But I'm nevertheless super excited to tell everyone I’m moving into a full-time role at Centessa $CNTA, working with
@SaurabhSahaMD
and team as Chief Innovation Officer
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$AMRN story is a great lesson for entrepreneurs & investors... if you can’t protect your idea you will suffer a fate more painful than failure: being right & watching everyone else harvest the benefits!
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The issue is not the adverse events, but our heightened sensitivity to them
If we are going to have this much debate over every few-in-a-million event, then we would never approve another drug
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Perhaps some of the people signing petitions against “vaccine passports” would like to explain the problem with them to me?
Because I think they are an excellent idea. Since everyone is being offered a vaccine, I fail to see how tying freedom to compliance is discriminatory
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@Tom_Slater_
@LozzaFox
A perfect summary of where we going wrong in the West
Tolerance of things that should never be tolerated; and a demonisation of the petty, the stupid and the personal opinion we are entitled to hold and express (even if other people dont like it)
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How can this be happening?
Even if
@DrMJoyner
were wrong (which he likely is not), this would still be utterly wrong-headed. Here we have a principled capable scientist saying what they believe to be true - if we cannot protect his right to do that, we are lost
@MayoClinic
punishes Prof
@DrMJoyner
for saying that transgendered athletes have an advantage due to testosterone while building a new 5 billion dollar campus: The love of money has destroyed the love of knowledge via
@VPrasadMDMPH
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The future of drug design are “smart” biologics - proteins, usually antibodies, engineered to deliver activity in the right place at the right time
It will be these agents, not gene or cell therapies or gene editing that dominate the 2040 medicine cabinet
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What is very noticeable is just how BIG these molecules are getting. It may allow access to interesting pharmacology but it will create huge (unassailable?) hurdles in development as drugs for many of them
Small Molecules of the Month - Apr. 2021 |
This month:
An inhibitor that "glues" KRAS to cyclophilin A
A targeted protein stabilizer
An RNA-modifying enzyme inhibitor
Wild!
#chemtwitter
#biotwitter
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This is an interesting statement
Whether its true, depends on what you believe “getting out of this” needs to look like
But 5-12yo are not cattle who should be vaccinated to “get us out of” anything. It is hard to argue it is the interest of the INDIVIDUAL child
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As Musk accuses unnamed employee of sabotage the parallels with the months before the fall of Theranos are getting scarily real $TSLA
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Three leading vaccine candidates (Oxford/$AZN, $PFE/$BNTX and $MRNA) all need a booster - dont lets under-estimate the logistical challenge of getting a material fraction of the population vaccinated ONCE. Two doses is twice the logistical challenge
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A short thread on de novo hit generation in small molecule drug discovery
I’m lucky enough to see first hand 10+ programs a year against different, mostly novel, targets - and there are some clear trends emerging about the best approaches
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@ProfKarolSikora
A few idiots flouting the rules makes headlines - but actually transmission of the virus depends on what the MAJORITY do
And all around me, I see people acting very sensibly
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Just a few words of caution on the impact Deepmind and Alphafold can have on drug discovery
(And to be clear I am incredibly impressed scientifically by what the team has done - this is not “criticism”, more “caveat emptor")
A 🧵
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Very interesting - and perhaps the best news of all - that the Pfizer-BioNTech vaccine was equally effective in the over-65s
For me, it was always highly likely many of the
#COVID
vaccines would work in younger people, but less certain in the older, most vulnerable population
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Drug R&D is a LONG game
You win not by being faster at any given point, but by making fewer mistakes
Doing it BETTER nearly always trumps doing it FASTER
Hence more resources can actually damage progress by going so fast you dont have time to think / miss the warning signs
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With the ground-breaking approval of Casgevy, the first CRISPR-based therapeutic, by
@MHRAmedicines
to treat beta-thalassemia its worth reflecting that CRISPR was only discovered in 2012
That only 11 years from first discovery to first approved medicine
Impressive!
$VRTX $CRSP
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One in five deaths worldwide due to
#sepsis
-
Thats more than all cancers combined. Are your R&D priorities correctly aligned?
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The accounts that make bio Twitter such a great place to be:
@AndyBiotech
@ethanjweiss
@michael_gilman
@JohnTuckerPhD
@LifeSciVC
@skathire
@adamjshay
@Biotech_Beast
@odibro
@PredatorDiaries
@MikeNGladstone
@daphnezohar
@zbiotech
Thanks for everything you share!
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@kelvmackenzie
First rule of insurance - there’s always an exclusion buried in the small print for any event that actually happens
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It’s quite amusing how much optimism there seems to be about finding treatments for
#COVID19
in a hurry. Worth remembering just how little progress we have made in a century looking for treatments for respiratory viruses (common cold, flu, RSV etc)
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Today would have been my dad’s 90th birthday
Unfortunately he died suddenly in 1987 at the age of 55 with a massive myocardial infarct secondary to CHD
Seems like a great moment to celebrate the progress we’ve made at saving others from the same fate
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@VPrasadMDMPH
@DrMJoyner
@nytimes
Completely agree.
This is truly shocking. What he said is factually accurate - how can society tolerate academic institutions attempting to silence academic opinions?
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All this discussion about whether couples who live apart can see each other or kids with separated parents can move between them is a complete red herring
These have irrelevant effects on median connectivity.
While we are running packed tube trains, leave these people alone
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I wish we had more insight into WHERE these 50,000 people a day are getting infected…
Is it at work? In the home, from relatives, or through illegal household-mixing? The fact we seem to have NO IDEA worries me
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Lots of people highlighting pessimistic estimates of duration of protection for
#COVID
vaccines - but the facts guides us in the opposite direction: Im optimistic for multi-year duration of protection
Why?
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What is striking about this is how SMALL the increase in odds of success is (2.6x is a small gain really)
And all the biggest drugs of the 21st Century have no real genetic target validation (statins, Plavix, Humira, PD(L)1s, Comirnaty, GLP1s and others)
Update on impact of genetic support for drug targets on probability of clinical development success
@Nature
👉2.6x higher odds of success
👉higher odds across all therapeutic areas
👉discovery of potential targets through genetics still not saturated
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Nice illustration of the impact of cheap capital: average size of VC investment rounds in biotech has gone up almost 400% in just five years!
Returns will likely decline by a similar factor - so watch out for the pain when capital cost eventually normalises
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I wonder how many failures it will take before $SRPT and their investors read my QJM Editorial from 2000 ()
It summarises the data that by the time muscle weakness manifests it is no longer driven by the lack of dystrophin
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I view deep understanding of statistics (ie deeper than that of those generating the data) as THE core competency of a biotech investor. It’s the only guide we have as to which “facts” to believe and which to ignore
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Very striking how “flat” (Ph1 = Ph2 = Ph3) all these pipelines are considering the inevitable attrition rates. Shows just how dependent pharma has become on clinical-stage acquisitions
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Dear Tory rebels: while no-deal
#brexit
MAY hit house prices, be in no doubt that a Corbyn government would destroy them (and NATO and much else you value besides…). Even if you fear no deal, it is better than any of the alternatives…
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As a VC, biotech operator AND exec chairman of a CRO (
@RxCelerate
) Id say these broad estimates of costs for out-sourciong key activities from
@celinehalioua
is pretty accurate - useful for those setting up a virtual/semi-virtual biotech
(h/t
@simonbayly
)
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@drrichjlaw
I dont think it’s the specifics that matter - it is hard to argue that the
#NHS
is well managed from any vantage point. But the failure to engage with
@ProfKarolSikora
over re-opening Rutherford Centres but not address so much waste is negligence bordering on criminal
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The obsession with “advanced therapeutics” particularly in the UK annoys me…
Theres nothing intrinsically valuable about doing something complicated. It does NOT make up for a lack of understanding of biology, which is the fundamental limitation on better therapeutics
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Am I the only one horrified by the sheer weight of capital flowing into biotech start-ups, as $50+m Series A’s become commonplace?
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I couldn’t disagree with this assessment more. Every biotech does all of these things
It is a tag laden with hubris and hype and serves no other useful purpose
recently changed my mind: techbio firms are a distinct species from biotechs, not just a rebrand
classification rules:
- use an in silico model & internal data corpus to develop otherwise intractable products
- explore hypotheses that maximize upside, rather than optimizing for…
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Not sure whether to be happy or sad that my
@forbeshealth
post about my January diet () has attracted more page-impressions in 12hrs than anything I ever wrote about biotech!
#DrugBaron
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As VCs we see way more poorly designed clinical trials than good ones - in normal times without pressure to act quickly
Not optimistic about the quality of many of the
#COVID19
trials now underway, sadly
Bad data arguably worse than none
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The speed of therapeutic innovation cominhg from RECOVERY trial is sensational!
This should be the model for every common disease from heart disease to Alzheimer’s, osteoporosis to IBD
Nothing would accelerate innovation for patients faster. Who’s going to be first?
⏩ New RECOVERY trial result.
Monoclonal antibody combination reduces deaths in seronegative patients hospitalised with COVID-19.
- 9785 patients randomised
- primary analysis population 3153 patients without own SARS-CoV2 antibodies detectable at randomisation (seronegative)
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Biggest concern is all this hype makes people focus on anti-amyloids again. Let’s remember even if replicated in Ph3 this is a paltry effect size. We still need to re-double our efforts on non-amyloid approaches to
#AD
$BIIB
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I do think healthcare professionals need to be particularly careful. It seems clear that severe symptoms result from high viral load. If the virus gets to very high copy number before your adaptive immune response kicks in you are at very high risk if ARDS
1/n
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If you only read one thing the week, make it this: Superb
@BMJ_latest
piece by
@scarlettmcnally
on exercise & ageing
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I found this so depressing. Why on earth would anyone not want their DNA to contribute to future medical advances? Think of it as a charitable donation. And to link it to the drug price debate is stupid and misleading
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Ok - so here it is... Divide & Conquer emerges from stealth to bring the concept of “cellular social networks” to oncology
How new
@Medicxi
company Divide & Conquer, co-founded by
@sciencescanner
, aims to capitalize on new biology that could prevent cancer cells from sharing resistance mechanisms via multicellular networks
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Picture is much more complex, and we dont yet have all the information needed to judge how this will shake down
But we do already know the Oxford/$AZN vaccine is likely to be an important component of the world-wide battle against
#COVID
- & possibly even the MOST important part
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Instead of all the focus on hydroxychloroquine - does it work or doesn’t it? - let’s focus on comparing strategies in critical care of
#COBID19
lung disease. Proning plus inhaled NO versus CPAP maybe? Cheap quick RCT might save way more lives than a drug...
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But still not as well (or certainly no better) than a six-monthly injection of inclisiran
So the question I still havent got my head round is WHY? Minor convenience seems a very poor reason for altering your genome and accepting even a theoretical risk of off-target edits
In vivo base editing works in humans!
Congratulations to
@KomorLab
,
@NicoleGaudelli
, and
@davidrliu
for advancing gene editing science and inventing base editing technology!
Great work by both the
@BeamTx
team and the Verve team to make it happen!
@skathire
and
@ambellinger
👏🎉
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“US buys almost all world’s upcoming supply of remdesivir”
Not a problem - we, in the UK, will stick with dexamethasone - since that actually works! Cheaper too...
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I wouldnt pay $1. If a simple genetic change was net beneficial evolution would have found it before science…
This kind of discussion belies the extent to which we misunderstand the nature of ageing
Would you pay $1 million for an unproven, untested anti-aging gene therapy?
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On my way to Paris to meet a team working on an intriguing approach to curing (yes, curing) all solid tumor types. Without doubt most exciting science I’ve seen in decades. Watch this space
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“The Cult of DNA-centricity” My latest post
@ForbesHealth
tries to explain why the genome is not the answer
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Once we acceot that we are vaccinating to prevent severe disease / death, and NOT in some vain chase to
#zerocovid
, then we can stop boosting
Oh, and with a nice mild, transmissable
#omicron
around, eveeryone will get a “natural” boost anyway!
3/3
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Please read. Ive been saying this for years - but a lot less eloquently!
Let’s play a little game.
Let’s say that you’re the CSO at a cancer pharma company, and you have to choose a target to go after.
Here’s a gene – high expression is associated with poor prognosis in brain cancer. Looks like a good candidate for an inhibitor right?
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Nice study of biases at work…
Our new preprint follows the top 10 newspapers before and after COVID when they give advice on avoiding the FLU
Guess what? Masks suddenly are in vogue, but weren't prepandemic. New data? Not at all-- Just new biases
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But there is no data that I have seen showing that the ability of the memory response to protect against severe illness/death has declined at all with time
Without such evidence, there is no justification for general use of boosters
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@BBCBreaking
So Sturgeon re-enstates large crowds outdoors in Scotland from Monday - effectively admitting the Scottish (and Welsh) Governments got this badly wrong in the first place
I wonder if there will be an apology?
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I’m sorry? Observational studies report ASSOCIATION- RCTs require CAUSATION. A negative result from an (appropriately designed) RCT tells you the association observed was spurious (confounded). What do the 43% think these study types show???
Do negative findings in a randomized trial reverse the positive findings from observational data?
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Huge pat on the back for Sanofi/Regeneron in delivering a high quality study of anti-IL6R in
#COVID19
lung disease.
The drug doesnt do anything, but at least we know that for sure
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I cant be the only one annoyed by the utterly pointless “Accept” box that pops up on every website you visit for cookies that you have to accept to access the content
I must accept a hundred a day
Whoever thought such a law benefited users was living in Narnia
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Enjoyed my first experience of
@BiotechCH
last night.
@cngarabedian
@daphnezohar
@bradloncar
deliver a great mix of info sharing and debate. As I said at the end “I’ll be back!”
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So here is my first attempt at an oil painting: Struie Hill Overlooking the Dornoch Firth
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Big congratulations due to
@MedicxiKevin
@J_S_Edwards
as Celgene acquire
@Medicxi
portfolio co Impact for $7B: $CELG
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@JohnCendpts
@AndyBiotech
Really surprised you say that John - I think
@andybiotech
has been pretty objective actually. There’s so much thoughtless pumping/flaming on biotwitter - but this wasn’t anything like that. In fact been one of my fav accounts on here this past few years...
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Wondering why we haven’t got a serology test for
#COVID19
in widespread use yet?
#DrugBaron
looks at why it’s such a challenge and why rushing out a poorly-characterised assay would dangerously muddy the waters rather than provide much-needed clarity:
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Really struggling to see how
@US_FDA
can need til 10th December to decide on EUA for $PFE vaccine…
Surely they have already done all the work on the CMC package, and all thats left is to review the Ph3 safety and efficacy data? Hard to see why that cant be done in a week...
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Dear
@bbchealth
- “antibodies fall rapidly after
#covid
infection” is not headline news, just GCSE biology. You don’t churn out Abs to an infection you no longer have... you just retain immunological memory
Articles like yours misinform & mislead
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Most of the excitement around KRAS inhibitors stems from their prior status as “undrugable” rather than their stellar clinical activity
The jury is out as to how much these “holy grails” might yet turn out to be damp squibs
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My thoughts exactly
@Erictopol
is not a scientist (or at least not an honest one) - but by masquerading as one, does a lot of damage
John Mandola and Eric Topol are both cardiologists
Yet, John is able to actually read a paper in
@LancetRespirMed
on MR post Covid and explain why it is worthless on todays
@Sensible__Med
, while Eric just keeps tweeting sensationalist & inaccurate summaries of articles.
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Quite
And they are not “free”. In addition to financial costs, they create a culture of fear and non-normality.
Doing things on a hunch made sense 18months ago as we learned about
#covid
- today, we need evidence and proper cost:benefit assessments
@VPrasadMDMPH
@mgtmccartney
@jeangra99179111
@drjohnm
This is a good time to remember that we have not trialed *any* school mitigation measures in the U.S.; HEPA filters, testing policies, quarantine policies, pods, NOTHING.
This is not what taking something seriously looks like.
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