1.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. https://sciencedirect.com/science/article/pii/S0960894X12003071?via%3Dihub…
2.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).
3.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-44152. 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.
4.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. https://patents.google.com/patent/WO2017049060A1/en…
5.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. https://thelancet.com/journals/lancet/article/PIIS0140-6736(16)30386-5/fulltext…
6. 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 https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018169946…
7.Early — Mid 2017: Clinical trial of GS-441524 in cats with FIP begins. Led by Niels Pedersen at UC Davis School of Veterinary Medicine.
8.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. https://science.org/doi/10.1126/scitranslmed.aal3653?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed…
9.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. https://science.org/doi/10.1126/scitranslmed.aau9242…
10.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. https://mutian.com/order (To be continued…)
https://www.sciencedirect.com/science/article/pii/S0960894X12003071?via%3Dihub
11.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). https://nejm.org/doi/full/10.1056/nejmoa1910993…
12.December 31, 2019: A cluster of pneumonia cases in Wuhan are reported to the WHO China County Office https://who.int/emergencies/disease-outbreak-news/item/2020-DON229…
13.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. https://nejm.org/doi/pdf/10.1056/NEJMoa2007016?articleTools=true…
14.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. https://nature.com/articles/s41422-020-0282-0… 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.
15.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. https://thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext…
16.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. https://nejm.org/doi/full/10.1056/nejmoa2007764…
17.March 3, 2020: Gilead initiates trial to investigate 5- versus 10-day treatment with remdesivir in hospitalized patients with severe COVID-19.
18.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. https://nejm.org/doi/full/10.1056/nejmoa2015301…
19.March 3, 2020: Gilead initiates trial to investigate 5- versus 10-day treatment with remdesivir in hospitalized patients with moderate COVID-19. (To be continued…) Credits: Authored by Victoria Yan.
20. 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. https://jamanetwork.com/journals/jama/fullarticle/2769871…
21.March 22, 2020: MD Anderson research labs shut down & I start thinking about remdesivir.
22. April 20, 2020: Wuhan Institute of Virology files provisional patent in China on (deuterated) GS-441524 prodrugs. https://patents.google.com/patent/CN112778310A/en…
23. 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. https://nature.com/articles/s41586-020-2423-5…
24. 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. https://statnews.com/2020/05/14/gilead-should-ditch-remdesivir-and-focus-on-its-simpler-safer-ancestor/…
25.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. ( Point to be noted : “Bay Area philanthropist”.., is it Steve Kirsch? (https://the-scientist.com/news-opinion/gilead-urged-to-explore-remdesivir-relative-as-covid-19-drug-67811…)
26.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.
27.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.
28.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.
29.June 1, 2020: Bay Area philanthropist reaches out to senior leadership at Gilead on our behalf to request a meeting on GS-441524.
30.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.
31.June 24, 2020: First meeting with 4 members of the Gilead scientific leadership.
32.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.
33.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. 34.July 8, 2020: Gilead announces initiation of phase 1 trial with inhaled remdesivir in COVID-19 outpatients.
35.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.
36.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.
37.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.
38.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.
39.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.
40.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
41.October 16, 2020: Bay Area Philanthropist reaches out to Gilead exec to probe options on next steps to quickly move GS-441524 forward.
42.October 30, 2020: Gilead shares data on head-to-head challenge study between GS-441524 and remdesivir.
43.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.
44.June 23, 2021: Gilead files WO patent describing the synthesis and application of new remdesivir prodrugs.
45.July 30, 2021: Gilead announces that it will discontinue development of inhaled remdesivir.
46.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.”
END