💊Exciting news today about another oral therapy for early COVID: reduced hospitalization & mortality.
Here’s a Deep dive 🧵 on the new PF-07321332 protease inhibitor (“Paxlovid”) & the very impressive results announced from the EPIC-HR trial.
TL/DR: this is a big deal. 1/
What the heck is PF-07321332?
All coronaviruses produce a polypeptide that must be cleaved by a protease into 11 proteins. Without this protease the virus can’t co-opt cellar machinery & reproduce.
PF-07321332 Inhibits the viral main protease (Mpro). 2/
Specifically PF-07321332 binds to the catalytic site of Mpro.
Mpro is a great target because there are unique features of Mpro not found in *any* human enzymes & because spike protein mutations wouldn’t confer resistance.
In contrast to other SARS-CoV-2 drugs (remdesivir, Molnupiravir) which are nucleoside analogs, protease inhibition (PI) should have fewer off target effects. (E.g. No risk of mutagenesis).
Building on work with SARS-CoV1 (which has a 100% identical Mpro catalytic site) researchers developed potent covalent inhibitors of the viral Mpro: PF-07321332
After development of candidate Mpro inhibitors in vitro, the drug showed promise in mouse models.🐁
First in human trials (NCT04756531) began in February 2021. These studies found an effective Cmax and tolerable AE profile.🤞 5/ medrxiv.org/content/10.110…
The Evaluation of Protease Inhibition in COVID-19 High Risk Patients (EPIC-HR) study was begun in July 2021.
It was a n=3000 blinded RCT comparing PF-07321332 vs placebo. It was performed at 359 sites in the 🇺🇸 & other countries (🇧🇷🇨🇴🇯🇵 🇲🇾🇰🇷 & others) 6/ clinicaltrials.gov/ct2/show/NCT04…
Sidebar: Why combine w/ ritonavir esp since lopinavir/ritonavir wasn't effective against COVID19?
They added Ritonavir not for anti-viral effects but to "boost" drug levels of PF-07321332 by inhibiting CYP3A. We do something analogous w/ "ritonavir boosted darunavir" in HIV.
7/
EPIC-HR enrolled "high risk" COVID19 patient w/i 5 days of symptoms.
Notably they are doing similar trials in standard risk pts (EPIC-SR) & post exposure prophylaxis (EPIC-PEP) 8/
The primary endpoint of EPIC-HR was hospitalization or death within 28 days of randomization.
Secondary endpoints were pretty much what you'd expect (resolution of symptoms, clearance of virus, longer term outcomes, and adverse effects). 9/
The trial record and statistical plan seem normal & rigorous.
As far as I can see no🚩 in the study design or protoocl changes. (admittedly I'm reading quickly & having worked overnight in the ICU!) 10/
The results of PF-07321332 vs placebo were impressive! So impressive that EPIC-HR was stopped early by IDMC/FDA at interim analysis.
Hospitalizations
6/607 (1%) vs 41/612 (6.7%) [p<0.0001]
Overall this was an 89% reduction in the composite outcome of death/hospitalization.
A NNT of 17 to prevent a hospitalization & a NNT of 62 to prevent a death.
& the pre-specified subgroup of patients who presented sooner (within 3 days of symptom onset) did even better.
12/
Only limited safety data provided:
Of 1881 pts, side effects "most of which were mild" were 19% w/ PF-07321332 vs 21% w/ placebo
There were fewer severe AEs w/ drug than placebo: 1.7% vs. 6.6%, & discontinuation due to side effect was more common with placebo: 2.1% vs. 4.1% 13/
Bottom line:
-the anti-viral PF-07321332 seems promising in vitro
-there were significant reductions in hospitalizations & mortality in a large phase 2/3 RCT; these are clinically meaningful effects
-I'm excited to see more data when they go to the FDA later this month!
14/14
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Did he have a head CT? What did it show?
Did he have stitches? Tetanus shot?
The NYT ran nonstop stories about Biden’s health after the debate but can’t be bothered to report on the health of someone who was literally shot in the head?
To the people in the replies who say it’s impossible because of “HIPPA” 1. I assume you mean HIPAA 2. A normal presidential candidate would allow his doctors to release the info. This is exactly what happened when Reagan survived an assassination attempt. washingtonpost.com/obituaries/202…
My advice to journalists is to lookup tangential gunshot wounds (TGSW).
Ask questions like:
- what imaging has he had?
- what cognitive assessments?
- has he seen a neurosurgeon or neurologist?
- he’s previously had symptoms like slurred speech, abnormal gait - are these worse?
If you intubate you need to read the #PREOXI trial!
-n=1301 people requiring intubation in ED/ ICU were randomized to preoxygenation with oxygen mask vs non-invasive ventilation (NIV)
-NIV HALVED the risk of hypoxemia: 9 vs 18%
-NIV reduced mortality: 0.2% vs 1.1%
#CCR24
🧵 1/
Hypoxemia (SpO2 <85%) occurs in 10-20% of ED & ICU intubations.
1-2% of intubations performed in ED/ICU result in cardiac arrest!
This is an exceptionally dangerous procedure and preoxygenation is essential to keep patients safe.
But what’s the *BEST* way to preoxygenate? 2/
Most people use a non-rebreather oxygen mask, but because of its loose fit it often delivers much less than 100% FiO2.
NIV (“BiPAP”) delivers a higher FiO2 because of its tight fit. It also delivers PEEP & achieves a higher mean airway pressure which is theoretically helpful! 3/
Results from #PROTECTION presented #CCR24 & published @NEJM.
- DB RCT of amino acid infusion vs placebo in n=3511 people undergoing cardiac surgery w/ bypass.
- Reduced incidence of AKI (26.9% vs 31.7% NNT=20) & need for RRT (1.4% vs 1.9% NNT=200)
Potential game changer!
🧵 1/
I work in a busy CVICU & I often see AKI following cardiac surgery.
Despite risk stratification & hemodynamic optimization, AKI remains one of the most common complications after cardiac surgery with bypass.
Even a modest reduction in AKI/CRRT would be great for my patients. 2/
During cardiac surgery w/ bypass, renal blood flow (RBF) is reduced dramatically. This causes injury, especially in susceptible individuals.
But what if we could use physiology to protect the kidneys?
Renal blood vessels dilate after a high protein meal increasing RBF & GFR! 3/
77 yo with respiratory distress, RR 30, SpO2 80% on non-rebreather at 15 lpm
CXR & TTE are unrevealing
pH 7.58 / PaCO2 24 / PaO2 >500 / HCO3 22
MetHb 0% CarboxyHb 0%
The ABG looks like this:
The answer is sulfhemoglobinemia.
Sulfhemoglobinemia is a *permanently* modified hemoglobin associated with exposure to TMP/SMX, dapsone, phenazopyridine, & other amino & nitro compounds.
It has an altered oxy-hemoglobin dissociation curve.
2/
Sulfhemoglobinemia is easily confused with methemoglobinemia. Both have very dark colored blood & present with cyanosis. Diagnosis typically requires a specialized lab.
Spoiler: you may have heard that SulfHb is green. It isn’t really. You’re thinking of Vulcans’ blood.