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Victoria Yan Profile picture
@victoriacyanide
Dec 28, 2022 • 16 tweets • 10 min read • Read on X
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When did @GileadSciences decide that #GS441524 hypothesis was valid? Clues in patent history🔍

While Gilead bashed GS-441524 in 2020, they quietly worked on oral prodrugs

Could we have had an oral COVID pill in late '20/early '21? 💊

I think YES 🧵1/16
worldwide.espacenet.com/patent/search?…
Patent on oral GS-441524 prodrugs has 1st priority filing on AUGUST 27, 2020. So they did not think the '524 hypothesis was worthless in 2020. 2/16
statnews.com/2020/05/14/gil…
Context: @Muller_Lab & I published an Opinion in @statnews urging Gilead to pursue dev of #GS441524 in May 2020 (above)

On June 24, 2020, we first met w Gilead science leadership, who indicated they were not interested. 3/16
medium.com/@victoriacyani…
AUG 27, 2020: 1st priority filing. Includes synthesis & in vitro characterization (RSV, SARS-2) of many ester prodrugs & bioavailability of the tr-ester in cyno.

Mono-iBu ester #obeldesivir (GS-5245) NOT included. 4/16

register.epo.org/documentView?n…
These data were later published in J Med Chem in April 2021 (first submitted Jan 2021) in the context of RSV. 5/16
pubs.acs.org/doi/10.1021/ac…
OCT 2020: Many emails later, we convinced Gilead leadership to run a head-to-head study comparing IV #remdesivir with GS-441524 in a monkey model of COVID

'524 showed similar/slightly superior activity, likely facilitating oral '524 program. 6/16
sciencedirect.com/science/articl…
OCT 30, 2020: We met to go over data. They maintained their position on the superiority of RDV. One of them offhandedly said, in ref to oral GS-441524, "we could just put the isobutyric ester on it."

From their summary, they seemed more interested in phosphate prodrugs. 7/16
MAR 17, 2021: 2nd priority filing. Includes synthesis of & incomplete in vitro characterization of obeldesivir (RSV only, no SARS-2 or CC50 data)

No in vivo PK for obeldesivir. 8/16
register.epo.org/documentView?n…
JUN 25, 2021: 3rd priority filing. Synthesis of other mono-esters with complete in vitro data in RSV & SARS-2.

F% characterization for tri-ester and obeldesivir across preclinical species.

Efficacy in ferret & mouse models of COVID. 9/16
register.epo.org/documentView?n…
JUL 30, 2021: Plemper lab posts preprint to Research Square on efficacy of tri-ester in ferret model of COVID. Funded by Gilead.

Gilead states they have no plans to pursue tri-ester

Means they likely decided on obeldesivir in late '20/early '21. 10/16
researchsquare.com/article/rs-662…
AUG 26, 2021: International filing on GS-441524 ester patent.

Most characterization on obeldesivir (#GS5245), with 2 synthesis routes, in vitro/in vivo efficacy, extensive PK, XRC data. 11/16
SEPT 17, 2021: Sheahan lab posts efficacy of tri-ester (GS-621763) in SARS-2 mouse models to bioRxiv.

GS-621763 shared w Sheahan lab via MTA. 12/16
biorxiv.org/content/10.110…
JAN 2022: Gilead states "oral remdesivir" GS-5245 (obeldesivir) in phase 1. 13/16
cnbc.com/video/2022/01/…
MAR 9, 2022: In NIH Filovirus Workshop, I found that GS-5245 is a GS-441524 prodrug, *NOT* an RDV prodrug, like they seemed to suggest to us back in Oct 2020. 14/16
medium.com/@victoriacyani…
NOV 2, 2022: Gilead begins ph3 double-blind RCT with GS-5245 (obeldesivir). 15/16
clinicaltrials.gov/ct2/show/NCT05…
ALL OF THIS TO SAY: while publicly bashing the GS-441524 hypothesis in spring 2020, Gilead was working on oral '524 prodrugs THIS WHOLE TIME!

Could've had an oral COVID tx ~2021!

Milking remdesivir profits, dragging their feet on this project🐄 16/16
s29.q4cdn.com/585078350/file…

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More from @victoriacyanide

Victoria Yan Profile picture
Apr 12, 2023
NEW OBELDESIVIR (OBV; GS-5245) DATA! $GILD

Ph1 PK/PD from @GileadSciences' @ECCMID poster.

OBV = OBVIOUS! 🙊😂 #GS441524 #GS5245

Key points in thread 🧵 1/13
https://t.co/zOpymoJLicaskgileadmedical.com/conferences/co…
First, this was a healthy volunteer PK study. Impt to point this out bc it was strange that 25% of pts in PBO grp had grade 2 AE 🧐.

Also, note the dosing grps. They tested QD & BID regimens. The ph3 dose is 350 mg BID but this wasnt actually tested here...2/13
...350 mg BID likely decided bc of decreased creatinine clearance (grade 2) at >500 mg in some pts. 3/13
Read 13 tweets
Victoria Yan Profile picture
Apr 11, 2023
FINALLY! @GileadSciences CONFIMRS #GS5245 = OBELDESIVIR!!

"Phase I trial, which involved 70 healthy adults, showed that obeldesivir reached sufficient concentrations in the blood and supports taking it without regard to food"

#GS441524 $GILD #COVID_19

reuters.com/business/healt…
You heard it here first!!!! (dec 2022!)
#GS5245 #GS441524 #obeldesivir
Read 4 tweets
Victoria Yan Profile picture
Jan 30, 2023
Since obeldesivir, figuring out the structure of undisclosed cmpds in the clinic has become my new hobby 🤠

So I'll periodically post structures of other cmpds here

I'll start w #VX548, a Nav1.8 inhibitor for treating pain by @VertexPharma $VRTX. Inspired by @cispt2 1/8
VX-548 is currently in ph3 for the tx of acute pain. From trials registry, the earliest trial date is on July 19, 2021. 2/8
A series of patents were recently published by Vertex on the same series of the inhibitors (Dec. 8, 2022)

These all have the same priority/filing/publish dates

Earliest priority traces back to June 4, 2021: ~1 mo. earlier than 1st trial reg (July 19, 2021) 3/8
Read 8 tweets
Victoria Yan Profile picture
Nov 29, 2021
BIG NEWS: deuterated #GS441524 tri-iBu ester (#VV116) is in clinical trials in Uzbekistan for #COVID19. Trials in China 🔜. Developed by the one and only *Wuhan Institute of Virology*. Deuterium was added to bypass @GileadSciences 💊 1/4
@ncats_nih_gov
shine.cn/news/nation/21… Image
Official article published in @cell_res in September 2021 by the folk at Wuhan Institute of Virology. Original @biorxivpreprint was published in November 2020. 2/4
nature.com/articles/s4142…
Chinese patent by the WIV first filed in Sept 2020. WO patent filed in April 2021. Gilead's 2009 patent on 524 and the 2016 patent on #remdesivir do not include any of the compounds described in the WIV patent. Does Gilead actually own any of these WIV compounds?? 3/4 ImageImage
Read 5 tweets
Victoria Yan Profile picture
Apr 9, 2021
First-in-Woman Safety, Tolerability, and Pharmacokinetics of Orally Administered #GS441524: A Broad-Spectrum Antiviral Treatment for #COVID19. A 🧵1/7 osf.io/am5s8/
Part 1 of the study: 750 mg GS-441524 was orally administered as a solution QD for 7 days. D1-5 were performed in the fasted state. D6-7 in the fed state. There was a slight food effect that seemed to hamper drug absorption. Cmax ~2.4-3 uM. AUC ~26-33 uM. 2/7
No AEs or lab abnormalities were observed in Part 1 of the study. Blood chemistry was normal. 3/7
Read 7 tweets
Victoria Yan Profile picture
May 14, 2020
Fun fact: #remdesivir is almost certainly not the species that reaches #COVID19 patients' lungs! Its nucleoside #GS441524 is. Wrote this piece for @statnews explaining this! @GileadSciences consider aerosolizing GS-441524 prophylaxis. Pls read and RT! 1/x

bit.ly/3dIc0Au
I've been reading a lot of general audience/science articles on #remdesivir. Many of these articles seem to confuse nucleoSIDES with nucleoTIDES. Here's the difference, feat. important figures. 2/x
#remdesivir is a nucleoTIDE monophosphate analogue. #GS441524 is a nucleoSIDE analogue. 3/x
Read 10 tweets

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