A partial account of GS-441524, remdesivir, and GS-5245
Victoria’s POV
In late January 2022, the CEO of Gilead Sciences, Daniel O’Day, announced that Gilead is “working on an oral form of remdesivir” that is “going into early-stage trials now.”
When asked on whether he was referring to inhaled remdesivir or a pill form, he said (timestamp @ 03:28),
“ We’re talking a tablet that you swallow. So what we’ve decided is that, given the fact that our tablet that you swallow was at about the same stage as the inhaled version, we’re putting all of our resources into the oral version.”
The big question about this drug, called GS-5245, is whether this was an oral version of remdesivir or its parent nucleoside, GS-441524.
On March 9, 2022, much of the speculation on the possible nature of was largely put to rest when the mechanism of bioactivation of GS-5245 was revealed at the 2022 Nex Gen Filovirus Workshop. The diagram depicted shows that GS-5245 is an oral prodrug that is designed to deliver the parent nucleoside, GS-441524, into systemic circulation.
Some background on me.
For two years, I, my colleagues, and a growing number of scientists and citizens have been advocating for clinical advancement of GS-441524 as an outpatient COVID-19 therapeutic. In May 2020, I published an opinion article in STAT News urging Gilead to develop GS-441524, the parent nucleoside of remdesivir, as an oral outpatient treatment for COVID-19. Remdesivir works by inhibiting the SARS-CoV-2 replication machinery in infected cells. To do this, it first has to be converted to its active metabolite within infected cells. While this conversion to the active metabolite occurs to some extent in patients administered remdesivir IV, an appreciable amount of remdesivir is prematurely cleaved to GS-441524 in the blood. GS-441524 and remdesivir form the same active metabolite that halts SARS-CoV-2 replication.
As a graduate student at MD Anderson, I happened to study the chemistry & pharmacology of the class of drugs to which remdesivir belongs, known as phosphate prodrugs. After reviewing the available data, I had concluded that GS-441524 would be superior to remdesivir for COVID-19 treatment for 3 reasons:
- GS-441524 can be administered orally because, unlike remdesivir, it is not susceptible to first-pass metabolism. This makes it amenable to outpatient administration.
- As its synthetic precursor, GS-441524 could be synthesized more quickly than remdesivir (you may recall that remdesivir manufacturing was a major concern early in the pandemic)
- GS-441524 had demonstrated in vitro efficacy against related coronaviruses (SARS-CoV, MERS-CoV) and had shown >80 % curative efficacy in cats infected with natural presentations of feline coronavirus, a uniformly fatal disease.
Timeline of some key events (1994 — present)
May 1994: A trio at Albert Einstein College of Medicine describes the synthesis and in vitro anticancer activity of a novel C-nucleoside in Tetrahedron Letters.
October 2009: Gilead patent describing a library of 1'-substituted derivatives of C-nucleosides, including GS-441524, is published.
April 2012: Gilead describes the in vitro activity of GS-441524 in Bioorganic Medicinal Chemistry Letters.
GS-441524 is referred to as compound 3a. The focus is on hepatitis C.
Some time between 2012 & 2014: Remdesivir (GS-5734) is first synthesized by Gilead and evaluated in vitro/in vivo against RNA viruses.
One of the main foci for development was respiratory syncytial virus (RSV).
Some time circa 2015: Niels Pedersen (UC Davis) reaches out to a Gilead contact to test a panel of compounds against feline coronavirus, including GS-441524
Pedersen is a leading researcher in feline infectious peritonitis (FIP, caused by feline coronavirus, FCoV). Despite working remarkably well against FIP, Gilead does not license GS-441524 to UC Davis.
September 2015: Gilead files a provisional patent and receives priority for a methods of use patent on remdesivir for the treatment of arenaviruses and coronaviruses
It is converted to an official WO patent in March 2017.
October 2015: Gilead presents protective efficacy of remdesivir (GS-5734) in rhesus model of Ebola virus disease at ID Week
October — November 2015: Scottish nurse who relapsed with Ebola is the first patient treated with remdesivir (GS-5734).
She was successfully treated (unclear to what extent remdesivir helped because N=1). However, her viral titers did drop precipitously on treatment. She also received the highest reported dose of IV remdesivir to-date (150 mg for 3 days, then 225 mg for 11 days). Case study was reported in the Lancet.
March 2016: Curative efficacy of remdesivir (GS-5734) in a rhesus model of Ebola is published in Nature.
Impressive study showing that the best activity was observed with 10 mg/kg remdesivir IV for 12 days. Synthesis of remdesivir is published in the Supporting Information — the first time it is disclosed in a peer-reviewed journal.
Early 2017: A pair of studies are published on the broad-spectrum antiviral activity of remdesivir (GS-5734) in vitro and its synthesis.
Synthesis, pharmacokinetics, and in vitro activity published in Journal of Medicinal Chemistry in January 2017. In vitro activities of remdesivir and GS-441524 are published in Scientific Reports in March 2017. Both studies were done in collaboration with CDC and/or US Army researchers
March 2017: Gilead receives priority date on a methods of use patent application on GS-441524 for treating feline coronavirus infections.
This was converted to an official patent in March 2018. Interestingly, Niels Pedersen, the leading feline coronavirus researcher at UC Davis, is listed as a co-inventor in the web description, but not the actual document (as far as I can see).
Early — Mid 2017: Clinical trial of GS-441524 in cats with FIP begins.
Led by Niels Pedersen at UC Davis School of Veterinary Medicine.
June 2017: Efficacy of remdesivir (GS-5734) against coronaviruses in mice is published by the Sheahan/Baric groups in Science Translational Medicine.
In vitro efficacy of remdesivir against SARS-CoV and MERS-CoV. In vivo prophylactic & therapeutic efficacy against mouse-adapted SARS-CoV.
March 2018: Efficacy of remdesivir (GS-5734) and GS-441524 against coronaviruses in vitro & mechanism of viral resistance published by the Baric/Denison group in mBio.
Remdesivir and GS-441524 tested in primary human airway epithelial (HAE) cells infected with either SARS-CoV or MERS-CoV
June 2018: In vitro efficacy against cat cells infected with feline coronavirus and in vivo pharmacokinetics of GS-441524 in healthy cats is reported by the Murphy/Pedersen group in Veterinary Microbiology.
February 2019: Niels Pedersen publishes >80% curative efficacy of GS-441524 in cats with FIP in Journal of Feline Medical Surgery
May 2019: Antiviral efficacy of remdesivir (GS-5734) in African green monkeys challenged with Nipah virus is published in Science Translational Medicine.
Study performed in collaboration with CDC and NIAID researchers.
August 8, 2019: Mutian Biotechnology Co Ltd files a Chinese provisional patent for bulk scale manufacturing of GS-441524.
Mutian is a well-known “black market” supplier of GS-441524 for cat owners
August 21, 2019: Media reports on Niels Pedersen’s advocacy to have GS-441524 licensed for FIP are published.
The article also describes FIP advocacy groups and the black market sale of GS-441524 to cat owners.
December 12, 2019: Clinical activity of remdesivir in patients with Ebola is published in the New England Journal of Medicine.
Remdesivir does not show antiviral or survival benefit at the dose examined. The study occurred between November 20, 2018 — August 9, 2019. PALM Trial (NCT03719586).
December 31, 2019: A cluster of pneumonia cases in Wuhan are reported to the WHO China County Office
January 2020: Remdesivir begins to be administered to patients with severe COVID-19 on a compassionate use basis.
The results from this open-label, non-placebo-controlled trial were later published in the New England Journal of Medicine in April 2020. No definitive conclusions could be made about its efficacy.
February 4, 2020: Wuhan Institute of Virology publishes the in vitro efficacy of remdesivir and hydroxychloroquine in SARS-CoV-2-infected VeroE6 cells in Cell Research.
Manuscript was received on January 25, 2020. 3 of the 10 authors later authored the WIV papers on GS-441524 prodrugs. These include Jia Liu, Gengfu Xiao, and Leike Zhang.
February 6, 2020: Capital Medical University in China initiates trial of remdesivir in patients hospitalized with severe COVID-19
Randomized, double-blind, placebo-controlled trial. Final report published in the Lancet in May 2020 concludes remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. Funded by Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project (NCT04257656).
February 13, 2020: Prophylactic efficacy of remdesivir in rhesus macaques challenged with MERS-CoV is reported in Proceedings of the National Academy of Sciences.
Study performed in collaboration between Gilead and NIAID researchers.
February 21, 2020: NIAID initiates a large randomized control trial to investigate remdesivir in patients hospitalized with severe COVID-19
Randomized, double-blind, placebo-controlled trial (ACTT-1; NCT04280705). Final report published in the New England Journal of Medicine in November 2020 concludes remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection
March 3, 2020: Gilead initiates trial to investigate 5- versus 10-day treatment with remdesivir in hospitalized patients with severe COVID-19.
Randomized, open-label, not placebo-controlled (SIMPLE-Severe; NCT04292899). Final report published in the New England Journal of Medicine in November 2020 finds no significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined.
March 3, 2020: Gilead initiates trial to investigate 5- versus 10-day treatment with remdesivir in hospitalized patients with moderate COVID-19.
Randomized, open-label, not placebo-controlled (SIMPLE-Moderate; NCT04292730). Final report published in JAMA in August 2020 concludes hospitalized patients with moderate COVID-19 randomized to a 5-day course of remdesivir had a statistically significantly better clinical status compared with those randomized to standard care at 11 days after initiation of treatment, but the difference was of uncertain clinical importance.
March 22, 2020: MD Anderson research labs shut down & I start thinking about remdesivir.
March 23, 2020: MD Anderson announces call for project proposals for select labs to assist with the COVID-19 effort. This is when the idea for GS-441524 first came to mind, for me.
MD Anderson selected two proposals to submit. We proposed orally bioavailable prodrugs of remdesivir, including GS-441524. Unfortunately, our proposal was not selected by the leadership.
March 26, 2020: I send an inquiry to Journal of Medicinal Chemistry on writing a mini-perspective on GS-441524 and orally bioavailable prodrugs of remdesivir as outpatient treatments for COVID-19
This was rejected after review because it was deemed too grant-like rather than a perspective. At the time, we were focused on prophylactic administration. With the efficacy of vaccines, we are now focused on (early) therapeutic administration.
April 20, 2020: Wuhan Institute of Virology files provisional patent in China on (deuterated) GS-441524 prodrugs.
April 22, 2020: Clinical benefit of remdesivir treatment in a rhesus model of COVID-19 is posted on the bioRxiv.
Study conducted in collaboration between Gilead and NIAID researchers. Final peer-reviewed study published in Nature in June 2020.
April 27, 2020: Efficacy and pharmacodynamics of GS-441524 and remdesivir against cells infected with SARS-CoV-2 is posted to the bioRxiv.
First report of that GS-441524 can form active metabolite in SARS-CoV-2-infected cells and exert antiviral activity in Vero E6 (African green monkey kidney) and Calu-3 (human lung cancer) cells. Study led by Andrea Pruijssers and conducted in collaboration between Gilead and the Sheahan/Baric/Denison groups. Final peer-reviewed study published in Cell Reports in July 2020.
May 1, 2020: Wuhan Institute of Virology publishes the co-crystal structure of the SARS-CoV-2 RNA-dependent RNA polymerase bound to RNA and remdesivir triphosphate (RTP; GS-443902) in Science.
Manuscript received on April 8, 2020.
May 14, 2020 (7:23 AM EDT): We publish the First Opinion piece in STAT News on why GS-441524 is better than remdesivir for COVID-19
Caused some kind of uproar in the community, was the top article on STAT for some time. Outlines the 3 points (see above) on the advantages of GS-441524 over remdesivir for COVID-19 treatment.
May 14, 2020: A prominent Bay Area philanthropist reaches out to Gilead leadership and then me after seeing the STAT article. Thus begins our interactions with the Gilead (scientific) leadership.
May 18, 2020: Friend of Bay Area philanthropist reaches out to (another) senior leadership at Gilead on our behalf to clarify reasons for not pursuing GS-441524
May 22, 2020: Bay Area philanthropist reaches out to executive leadership at Gilead on our behalf to ask for a brief meeting on GS-441524
Additional context, Florian & I had been in several ongoing email debates with researchers at the Gates Foundation/Hopkins/Northwestern about the merits of GS-441524. Proposing GS-441524 appeared to be counter-intuitive to the wisdom of the field, which could explain some researchers’ skepticism.
May 22, 2020: Preliminary report from ACTT-1 study of remdesivir in hospitalized patients with severe COVID-19 is published in the New England Journal of Medicine.
Randomized, double-blind, placebo-controlled trial from NIAID (ACTT-1; NCT04280705) finds shortened time-to-recovery in the remdesivir-treated group.
May 22, 2020: UC Davis publishes a case series on the curative efficacy of GS-441524 in neurological FIP in 3/4 cats treated in Journal of Veterinary Internal Medicine.
Manuscript received December 20, 2019.
May 27, 2020: A health researcher from Public Citizen reaches out to us. These discussions eventually lead to our letter to the DHHS leadership in August 2020.
June 1, 2020: Bay Area philanthropist reaches out to senior leadership at Gilead on our behalf to request a meeting on GS-441524.
June 11, 2020: The Bay Area Philanthropist is interested in helping us move GS-441524 to phase 1 and gave us some funds to conduct key preclinical studies to establish proof-of-concept.
We reached out our translational science/drug development arm at MD Anderson for help but unfortunately they were not interested.
June 23, 2020: Our Viewpoint in ACS Medicinal Chemistry Letters is published.
June 24, 2020: First meeting with 4 members of the Gilead scientific leadership.
This meeting was rescheduled twice and incidentally occurred 1 day after Gilead got the green light from the FDA to begin testing inhaled remdesivir in phase 1 trials. We presented the case for GS-441524 based on published data and they ultimately said that they did not choose to move forward with GS-441524 because of acute hematuria observed in cynomolgus macaques. Later, they said that acute hematuria was only observed in cynos after 20 mg/kg IV GS-441524 due to unknown etiology. This was not observed in other non-human primate species.
July 4, 2020: I reach out to a professor at Harvard who is part of the Scientists to Stop COVID-19 to gather support for advancing GS-441524 to the clinic.
July 8, 2020: Gilead announces initiation of phase 1 trial with inhaled remdesivir in COVID-19 outpatients.
July 20, 2020: We discuss with the leadership of the large Indian generic manufacturing company, Cipla, to try and initiate cGMP manufacturing of GS-441524.
Since Gilead had signed a licensing agreement for remdesivir to be produced by LMICs and that GS-441524 is an intermediate in remdesivir’s synthesis, we hoped that Cipla might be able to make progress with GS-441524 more quickly than in the U.S. While there was a lot of interest, it seems Cipla was concerned about overstepping boundaries with Gilead and this ultimately did not go anywhere.
July 23, 2020: Gilead says they’re going to conduct a head-to-head challenge experiments between remdesivir and GS-441524 in an African green monkey model of SARS-CoV-2
We continued to make the case for GS-441524 over email before then and thereafter.
July 28, 2020: NCATS reaches out to discuss GS-441524 development.
This was pre-Public Citizen letter.
July 28, 2020: We send a white paper on GS-441524 to DHHS through a mutual friend. Cipla indicates their interest in replacing hydroxychloroquine with GS-441524 in their the global clinical trail.
Unfortunately the Cipla initiative falls through.
August 2, 2020: We inform the Gilead folk about NCATS’ interest in possibly developing GS-441524.
August 4, 2020: Joint letter with Public Citizen to DHHS officials and Gilead CEO urging investigation/advancement of GS-441524 for COVID-19 treatment
Receives media coverage from STAT, The Guardian, Chicago Tribune, among others.
August 19, 2020: We ask Gilead if we can obtain a Letter of Authorization to cross-reference the data they have on file with the FDA on GS-441524 as part of their regulatory filings for remdesivir.
For some months prior, we had been communicating with the FDA and some of the leadership at MD Anderson in an effort to try and move GS-441524 through IND and into phase 1. Interestingly enough, while Gilead was receptive to this idea, the MD Anderson leadership did not want to proceed. This email thread spanned a few weeks.
August 20, 2020: (Now former) Director of NCATS responds to our joint letter with Public Citizen, agreeing that the GS-441524 is valid and stating that they will independently pursue this hypothesis.
September 25, 2020: Merdad Parsey (Gilead’s CMO) gives a lecture to his alma mater, University of Maryland, and answers questions about GS-441524 from the audience Q&A.
Notable timestamps:
[1:08:30] Now we’re going back, obviously, to re-evaluate that [GS-441524] and we’ll look at that and it’s something that we’re going to test. I think it’s an interesting hypothesis, it’s good to speculate on that. The only way to know is to test it. We’re going to test it and we’re going to see if we can show whether that precursor can have as good of a benefit, not quite as good, better. And if it’s better, we’ll be crazy not to push it forward. So, we will determine whether that’s true or not.
[1:09:10] The FDA doesn’t regulate animal medicines. We have worked with — and Gilead doesn’t do animal health; it’s not something we do. We have partnered with others to make it available and my understanding is — again, this is me getting out of my (inaudible), I don’t know the details here because we’ve been so focused on human disease — I believe, though I could be wrong, so I won’t speculate. We have worked with others to make it available and actually establish that and make it available if it is that effective. Those aren’t trials that we’ve run and they’re not data that we have access to other than the publications that are out there. So, we’re not in the way of getting that approved to people who want to use it for veterinary uses.
September 27, 2020: Wuhan Institute of Virology updates their patent application GS-441524 prodrugs.
Application filed by Shanghai Institute of Materia, Medica of CAS, Wuhan Institute of Virology CAS
October 2, 2020: NCATS releases first set of single-dose PK data on GS-441524 in preclinical species on the NCATS OpenData Portal
October 16, 2020: Bay Area Philanthropist reaches out to Gilead exec to probe options on next steps to quickly move GS-441524 forward.
October 23, 2020: Gilead informs us that they have the data on GS-441524 vs. remdesivir in a SARS-CoV-2 African green monkey model.
20 mg/kg IV GS-441524 versus 10/5 mg/kg IV remdesivir, administered 8 hours post-infection. GS-441524 was administered via IV instead of PO due to poor bioavailability/drug exposure in non-human primates.
October 27, 2020: Shenzhen group posts a preprint to bioRxiv on the in vitro and in vivo PK & efficacy of GS-441524 in SARS-CoV-2 and MHV mouse models. This was later published in Journal of Medicinal Chemistry on February 1, 2021.
Highlighted authors are those who co-authored the mono-isobutyrl prodrug of GS-441524 (ATV006) in Cao et al. bioRxiv (2021).
October 30, 2020: Gilead shares data on head-to-head challenge study between GS-441524 and remdesivir.
20 mg/kg IV GS-441524 and 10/5 mg/kg remdesivir show similar viral load reduction in bronchial alveolar lavage fluid after the 5-day study. Even though our conversations with them were not marked as confidential (with the exception of 1 slide, which is not included in this timeline), not showing actual data here because it’s not mine to show. Was also requested not share (below). At the end of this meeting, we asked whether they would be willing to license GS-441524 to us at MD Anderson to develop (and then return to them) and they said no.
November 2, 2020: Wuhan Institute of Virology posts a preprint to bioRxiv describing the in vitro efficacy and in vivo PK of deuterated GS-441524 (prodrugs).
April 9, 2021: I post the first in woman study on orally administered GS-441524 to OSF Preprints (NCT04859244)
Referred to in the Cox et al. Nat Comm. (2021) paper in the reviewers’ comments.
April 9, 2021: Gilead publishes (old) data on GS-441524 and remdesivir in an African green monkey model of RSV while also describing PK/PD for both species, to justify their decision to advance remdesivir.
April 28, 2021: First public report of the anti-SARS-CoV-2 activity of GS-441524 in primary human airway epithelial cells in vitro posted to bioRxiv. This was later published in Antiviral Research on June 26, 2021.
Co-authored by Gilead scientists. I asked one of the authors of their thoughts and this is what they said (right).
April 29, 2021: NCATS updates OpenData Portal with 7-day dose range finding studies in rats, dogs, and cynomolgus macaques.
June 3, 2021: Shenzhen group files Chinese patent application on crystal form of isobutyric prodrug of GS-441524.
Assigned to Pingshan Institute Of Biomedicine Southern University Of Science And Technology.
June 7, 2021: UC San Diego group publishes on orally bioavailable lipid prodrug versions of remdesivir to bioRxiv. This was later published in Antimicrobial Agents & Chemotherapy on September 17, 2021.
June 16, 2021: In response to some questions I asked on May 28, 2021, the FDA states that the 505(b)2 NDA path is possible for development of GS-441524.
505(b)2 is an accelerated path for drug development that principally relies on demonstration of PK/PD bioequivalence in preclinical species and humans. I relayed this information/response to NCATS and Gilead.
June 23, 2021: Gilead files WO patent describing the synthesis and application of new remdesivir prodrugs.
July 30, 2021: Georgia State University group posts the antiviral activity of a tri-isobutyrl prodrug of GS-441524 (GS-621763) in vitro and in a ferret model of SARS-CoV-2 to Research Square. This was later published in Nature Communications on November 5, 2021.
Co-authored by Gilead scientists.
July 30, 2021: Gilead announces that it will discontinue development of inhaled remdesivir.
Daniel O’Day: We have decided not to move forward with an inhaled formulation of remdesivir based on the results of our initial proof-of-concept study, suggesting sub-optimal lung disposition.”
August 10, 2021: CDC, in collaboration with the UC San Diego group, describes the broad-spectrum antiviral activity of orally bioavailable phospholipid prodrugs of GS-44124 in a preprint to bioRxiv. This was later published in Microbiology Spectrum on November 24, 2021.
September 17, 2021: We publish our mini-review, “Why Remdesivir Failed…” in Antimicrobial Agents & Chemotherapy.
First online in July 2021.
September 17, 2021: UNC Chapel Hill group publishes the antiviral efficacy of a tri-isobutyrl prodrug of GS-441524 (GS-621763) in a mouse model of SARS-CoV-2 to bioRxiv.
Co-authored by Gilead scientists. With head-to-head comparison against molnupiravir (MPV).
September 28, 2021: Wuhan Institute of Virology publishes in vitro efficacy and in vivo PK of a tri-isobutyl prodrug of deuterated GS-441524 (VV116) in Cell Research.
Manuscript was received on April 21, 2021. VV116 is X6.
October 4, 2021: Vigonvita Life Sciences and Junshi Biosciences announce they will jointly undertake the clinical development and industrialization of VV116.
October 14, 2021: Shenzhen group posts a preprint to bioRxiv describing the 5' isobutyric ester of GS-441524 (ATV006).
Describes their SAR, in vitro activity against SARS-CoV-2 variants, single dose PK in rats & monkeys, tissue distribution in mice, and anti-SARS-CoV-2 activity in an ACE2 humanized and Ad5-hACE2 mouse model.
October 28, 2021: Wuhan Institute of Virology files WO patnet on VV116 and other derivatives.
November 9, 2021: I ask Gilead about GS-441524 prodrug situation & they say don’t disclose any information that has not been published.
November 24, 2021: VV116, the tri-isobutyl ester of deuterated GS-441524 enters clinical trials in Uzbekistan.
December 30, 2021: Gilead publishes a study in Science Translational Medicine on the antiviral efficacy of inhaled remdesivir in an African green monkey model of COVID-19.
Similar antiviral efficacy as IV remdesivir. Paper first submitted on August 10, 2021.
December 31, 2021: VV116 receives EUA in Uzbekistan
January 10, 2022: NIAID, in collaboration with Gilead, publishes the efficacy of subcutaneously administered remdesivir in a rhesus macaque model of COVID-19 in Antiviral Research.
10/5 mg/kg dosing regimen. Reduced signs of respiratory disease and a lower, but not statistically significant, reduction in viral replication in the lower respiratory tract compared to vehicle control group.
January 15, 2022: KU Leuven posts a preprint on bioRxiv showing that GS-441524 retains activity against SARS-CoV-2 variants of concern, including Omicron, in vitro.
This was later published in Antiviral Research on January 24, 2022.
January 21, 2022: Vigonvita Life Sciences posts phase 1 multiple ascending dose trial of VV116 in healthy volunteers.
Tri-ester deuterated GS-441524 developed in collaboration with the WIV.
January 21, 2022: Gilead announces in a press release that they are working on their oral COVID-19 antiviral, GS-5245.
February 2, 2022: Vigonvita Life Sciences posts phase 1 trial of VV116 to examine the food effect on drug absorption in healthy volunteers.
Tri-ester deuterated GS-441524 developed in collaboration with the WIV.
February 7, 2022: NCATS posts a preprint to bioRxiv on in vivo PK and in vitro ADME of GS-441524.
Write-up of the data posted to the NCATS OpenData Portal.
February 7, 2022: Vigonvita Life Sciences posts phase 1 single ascending dose trial of VV116 in healthy volunteers
Tri-ester deuterated GS-441524 developed in collaboration with the WIV.
February 10, 2022: Gilead posts a preprint to bioRxiv also showing that remdesivir and GS-441524 retain activity against SARS-CoV-2 variants of concern.
First time a Gilead corresponding-authored paper puts GS-441524 in the title.
February 16, 2022: Shanghai JunTop Biosciences takes over late-stage clinical development of VV116 and posts a phase 2/3 outpatient trial of VV116 (now called JT001) for early treatment of COVID-19.
2,000 participants. Either 200 mg BID for 5 days or 400 mg BID for 5 days.
February 17, 2022: Gilead presents in vivo efficacy data on GS-5245 in 3 preclinical models of SARS-CoV-2 during their Virology Day.
“For investor use only; not for promotional use”
February 21, 2022: Gilead publishes an editorialized history of remdesivir development in ACS Medicinal Chemistry Letters.
To justify the use of phosphoramidate prodrugs like remdesivir for non-hepatic diseases.
March 9, 2022: Gilead presents the bioactivation scheme of GS-5245 at the 2022 NexGen Filovirus Workshop.
Structure of GS-5245 still not disclosed.
March 15, 2022: Shanghai Vinnerna Biosciences Co. posts a phase 3 outpatient trial of JT001 (VV116) compared to favipiravir.
640-patient trial. Interestingly, they are doing a loading/maintenance dose schedule with JT001 a lá remdesivir regimen. 600 mg BID on Day 1 followed by 300 mg BID on Days 2–5. Press release.
March 16, 2022: Vigonvita publishes the results of the single ascending dose and multiple ascending dose phase 1 trials in healthy Chinese participants in Acta Pharmacologica Sinica.
March 16, 2022: Junshi Biosciences announces first patient dosed in China in phase 3 clinical trial of VV116 in treatment of moderate to severe COVID-19
