COVID-2019 infections
In July 2020, the European Commission granted conditional marketing authorization for remdesivir for the treatment of COVID-2019 infections in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen. Earlier, in June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency's (EMA) adopted a positive opinion recommending the granting a conditional marketing authorisation (CMA) to remdesivir. The company will have to submit the final reports of the remdesivir studies to the Agency by December 2020, and further data on the quality of the medicine, as well as the final data on mortality, by August 2020. However, in October 2020, EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) initiated the review of a safety signal to assess the reports of acute kidney injury in few patients who were administered remdesivir for the treatment of COVID-2019 infections. The outcome of the PRAC’s review will be communicated after reviewing any new information that is available through monthly summary safety reports, periodic safety update reports, and signal detection [16] . Previously in June 2020, the EMA had received an application for CMA of remdesivir and had formally started its evaluation. At the conclusion of the first cycle of the rolling review in May 2020, the CHMP invited the company to submit further data together with an application for a conditional marketing authorisation. Also, EMA’s committee for medicines for children (PDCO) rapidly issued its opinion on the company’s paediatric investigation plan (PIP). Earlier, the CHMP started a rolling review of data on the use of remdesivir based on preliminary results from the NIAID- ACTT study [see below], which suggested a beneficial effect of remdesivir in the treatment of hospitalised patients with mild-to-moderate or severe COVID-2019 infections [17] [18] [19] [20] .
In October 2020, US FDA approved remdesivir (Veklury®) for the treatment of COVID-2019 infection in patients (12 years of age and older and weighing at least 40 kilograms) requiring hospitalization, and subsequently launched the product in the US. The FDA granted this application Fast Track and Priority Review designations. The Agency also granted this application a Material Threat Medical Countermeasure Priority Review Voucher, which provides additional incentives for certain medical products intended to treat or prevent harm from specific chemical, biological, radiological and nuclear threats [21] [22] [23] . In August 2020, Gilead completed the submission of a rolling NDA to the US FDA, seeking approval for usage of remdesivir (Veklury®), for the treatment of patients with COVID-2019 infections. The completion of this filing constituted the final tier of the submission, that was initiated in April 2020. The filing was supported by data from two phase III company-conducted drug trials, along with a phase III study conducted by National Institute of Allergy and Infectious Diseases (NIAID) [see below]. Drug treatment in these studies manifested faster recovery times relative to placebo, with comparable clinical improvements witnessed with both 5-day or 10-day treatment duration. Both treatment groups were reflective of a well-tolerated safety profile for the drug, bereft of new safety signals [24] .
In October 2020, the US FDA revised the Emergency Use Authorization (EUA) for remdesivir to remove the uses that are approved under Gilead’s New Drug Application (NDA). Thus, the EUA for Veklury continues to authorize Veklury for emergency use by licensed healthcare providers for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. In August 2020, the US FDA expanded the scope of the emergency use authorization for remdesivir to include treatment of hospitalised adult and paediatric patients with suspected or laboratory-confirmed COVID-19, irrespective of their severity of disease, regardless of the need for supplemental oxygen. Earlier, in May 2020, the US Food and Drug Administration (FDA) granted an emergency use authoristion to remdesivir for the treatment of suspected or laboratory-confirmed severe COVID-19 infections in adults and children with low blood oxygen levels or needing oxygen therapy or more intensive breathing support such as a mechanical ventilator. The drug is administered via intravenous infusion and is supplied either as an injection, 100mg, lyophilised powder, or as an injection, 100mg/20 mL (5mg/mL), concentrated solution [25] [26] [7] [27] [28] .
In June 2020, the US FDA reported that it is revising fact sheet for health care providers to state that administration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended as it may result in reduced antiviral activity of remdesivir. However, US FDA is not aware of any instances of reduced activity occurring in clinical setting and it will continue to evaluate all the data related to remdesivir. The FDA has also revised the fact sheet for health care providers to clarify dosing and administration recommendations and to provide additional safety data and supporting data from clinical trials [29] .
In May 2020, Gilead Sciences announced that Japanese Ministry of Health (MHLW) has granted regulatory approval of Venklury® (remdesivir) as a treatment for COVID-2019 infections under an exceptional approval pathway. The exceptional approval was granted due to the COVID-19 pandemic and references the Emergency Use Authorization of remdesivir in the US. The approval was granted on the basis of clinical data obtained from the phase III SIMPLE trial (see below) and from Gilead's compassionate use program, that included patients from Japan [30] .
In June 2020, The Health Sciences Authority (HSA), in consultation with its Medicines Advisory Committee, granted conditional approval for remdesivir. As part of the conditional approval, Gilead is required to collect the relevant safety data and to monitor the use of remdesivir. HSA will also require data from ongoing clinical studies to be submitted post-approval to ensure the continued safety and efficacy of the product. Earlier in March 2020, HSA initiated an early access of remdesivir to COVID-19 patients in Singapore through the expeditious evaluation and approval of its use in clinical trials. Gilead filed for registration of remdesivir in Singapore in May 2020 [31] .
In September 2020, Dr Reddy's Laboratories announced the launch of remdesivir for restricted emergency use, under a brand name Redyx® in India for the treatment of COVID-2019 infections. The Drug Controller General of India (DCGI) granted regulatory approval for restricted emergency use to remdesivir, for the treatment of suspected or laboratory confirmed COVID-2019 infections in adults and children hospitalised with severe disease in June 2020 [32] [33] [34] .
In June 2020, the Taiwan Food and Drug Administration (TFDA) of the Ministry of Health and Welfare (MOHW) conditionally approved remdesivir for patients with severe SARS-CoV-2 infection, according to the Article 48-2 of Pharmaceutical Affairs Act, provided that the pharmaceutical company would implement a risk management plan (RMP) to ensure the safety after the importation. Earlier in May 2020, TFDA hold a meeting and invited pharmaceutical and clinical experts to discuss the application and approval requirements of remdesivir [35] .
As of July 2020, the United Arab Emirates’ Ministry of Health and Prevention approved remdesivir for the treatment of patients with COVID-2019 infections [17] .
In March 2020, the US FDA granted orphan drug designation to remdesivir for the treatment of of COVID-2019 infections. However the status was withdrawn by the US FDA in the same month following submission of a request by Gilead to the US FDA to rescind the orphan drug designation [36] [37] [38] .
In October 2020, the University of Minnesota, the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institutes of Health (NIH), initiated a phase III ITAC trial to evaluate the safety, tolerability and efficacy of anti-coronavirus hyperimmune intravenous immunoglobulin (hIVIG) versus placebo, along with remdesivir as standard of care, in adult patients hospitalised for COVID-19 and have had symptoms for 12 days or fewer without life-threatening organ dysfunction or end-organ failure (INSIGHT013; EudraCT2020-002542-16; INSIGHT 013; NCT04546581). The Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) trial is a double-blind, placebo-controlled, randomised, adaptive and enrolling approximately 500 patients in the US, Mexico and 16 other countries in Africa, Asia, Europe, North America and South America. The primary outcome of the trial is to compare the health status of participants in each group on day seven, based on an ordinal outcome with seven mutually exclusive categories ranging from no limiting symptoms due to COVID-19, to death [39] . Emergent BioSolutions [see adis profile 800057829] , Grifols [see adis profile 800057941] and, CSL Behring with Takeda [see adis profile 800057734] will provide anti-coronavirus hIVIG for the trial. In October 2020, NIAID announced that primary analysis was planned after all participants finish 28 days of follow-up. An independent data and safety monitoring board (DSMB) will review interim safety and efficacy data to ensure patient well-being and safety as well as study integrity [40] .
In September 2020, Gilead Sciences initiated a phase III trial to evaluate the efficacy of remdesivir (RDV) in reducing the rate of hospitalisation or death in non-hospitalised participants with early stage coronavirus disease 2019 (COVID-19) and to evaluate the safety of RDV administered in an outpatient setting (NCT04501952; EudraCT-2020-003510-12; GS-US-540-9012). The randomised trial intends to enrol approximately 1230 patients in the US and in the UK [41] .
In August 2020, National Institute of Allergy and Infectious Diseases (NIAID) initiated the phase III ACTT-3 trial to evaluate safety and efficacy of remdesivir with interferon beta-1a [see Adis Insight drug profile 800007022] in patients with COVID-2019 infection (NCT04492475; 20-0006 ACTT-3). The randomised, double-blind trial intends to enrol approximately 1 038 adults and the elderly patients in the US, Japan, South Korea, Mexico and Singapore [42] . In September 2020, National Institute of Allergy and Infectious Diseases announced that the trial will no longer recruit severely ill COVID-19 patients after an interim review of 266 patients safety data by Data and Safety Monitoring Board (DSMB), however the study will continue to enrol hospitalised patients on low-flow oxygen and those not requiring supplemental oxygen. In October 2020, NIAID disclosed that in hospitalised patients with COVID-19 and lower respiratory tract involvement who received remdesivir had a statistically significant shorter time to recovery compared to patients who received placebo [43] [40] .
In May 2020, Roche in collaboration with Gilead Sciences initiated the phase III REMDACTA trial to evaluate the safety and efficacy of tocilizumab [see Adis Insight drug profile 800010359] plus remdesivir, versus placebo plus remdesivir in hospitalised patients with severe COVID-19 pneumonia (WA42511; EudraCT2020-002275-34; NCT04409262). The randomised, double-blind trial intends to enroll approximately 450 patients in the US, Canada, Europe and might expand to Brazil [44] [45] .
In April 2020, Gilead Sciences and University of Helsinki initiated the phase III SOLIDARITY Finland trial to assess the efficacy and safety of remdesivir and hydroxychloroquine compoared with standard of care in patients with COVID-2019 infections (EudraCT2020-001784-88; WHO-FIN-COVID-19). The main objective of the trial is to investigate effect on allcause in-hospital mortality compared to standard of care. The randomised trial intends to enrol approximately 664 patients in Finalnd [46] .
In March 2020, Sunnybrook Health Sciences Centre initiated the phase II Canadian Arm of the SOLIDARITY Trial (CATCO) trial to evaluate the safety and efficacy of standard-of-care products plus remdesivir or hydroxycholoroquine or lopinavir/ritonavir (2114; NCT04330690). The adaptive, randomised, open-label, controlled clinical trial, in collaboration with countries around the world through the World Health Organization intends to enrol approximately 2900 patients in Canada [47] .
In March 2020, Institut National de la Santé Et de la Recherche Médicale (INSERM) and Gilead Sciences initiated the phase III DisCoVeRy trial to assess safety and efficacy of remdesivir and other therapeutics including hydroxychloroquine, lopinavir/ritonavir compared with standard of care (NCT04315948; C20-15; EudraCT2020-000936-23). The primary endpoint of study is to determine the percentage of patients reporting each severity rating on a 7-point ordinal scale in 15 days. The randomised, adaptive trial intends to enrol approximately 3300 patients in France, Luxembourg, Austria and will expand to other parts of Europe [48] [49] .
In March 2020, Gilead Sciences initiated an expanded access treatment protocol for remdesivir for the treatment of COVID-19 infections in the US, the UK, Belgium, Canada, France, Germany, Italy, Israel, Netherlands, Romania, Spain, Switzerland, Australia, Austria, Cyprus, Croatia, Denmark, Estonia, Greece, Hungary, Ireland, Iceland, Czech Republic, Poland, Portugal, Slovakia and Slovenia (GS-US540-5821; EudraCT2020-001453-49; NCT04323761). In April 2020, Froedtert & the Medical College of Wisconsin granted an approval for the enrollment in the expanded access programme [50] [51] [52] .
In June 2020, Gilead Sciences completed the first phase III SIMPLE trials that evaluated the safety and efficacy of both a 5-day and a 10-day dosing regimen of remdesivir administered intravenously in patients with severe manifestations of COVID-19 (NCT04292899; GS-US-540-5773; EudraCT2020-000841-15; SIMPLE-severe). The trial was initiated in March 2020 and recruited 4891 patients globally including Germany, Spain, Italy, the Netherlands, the UK, Sweden, the US, Hong Kong, South Korea, Singapore, China, Taiwan, France, Japan and Switzerland. In April 2020, the company reported that the study was stopped in patients with severe symptoms due to delayed enrollment. However in June 2020, Gilead announce addition of expansion phase of the study was added to enroll up to 5 600 additional patients, including those on mechanical ventilation. In April 2020, efficacy and safety data from the trial was released by Gilead Sciences. In May 2020, Gilead announced that the data from the SIMPLE-Severe study support treatment of some patients for 5 days rather than 10 days, depending on clinical status. In July 2020, efficacy data from the trial were released by Gilead Sciences. In October 2020, updated efficacy data from the trial were presented at the IDWeek 2020 (IDW-2020) [53] [54] [55] [56] [48] [57] [58] [59] .
In June 2020, Gilead Sciences completed the second SIMPLE trial that evaluated the safety and efficacy of a 5-day and a 10-day dosing regimen of remdesivir administered intravenously in patients with moderate manifestations of COVID-19, compared with standard of care (NCT04292730; GS-US-540-5774; EudraCT2020-000842-32; SIMPLE-moderate) . The trial enrolled 1113 patients . Previously in April 2020, Gilead sciencs announced that the trail met its primary endpoint in China, France, Germany, Hong Kong, Iran, Italy, Japan, Netherlands, Scotland, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, USA. Gilead Sciences has donated remdesivir and provided scientific input for these studies. In June 2020, Gilead Sciences release data from the trial [56] [60] [61] [62] . In August 2020, updated results from the trial were released by the company [26] .
In October 2020, Gilead Sciences released final results and reported that the phase III ACTT-1 trial met its primary endpoint, demonstrating remdesivir plus standard of care was superior in shortening the time to recovery through Day 29 compared with placebo plus standard of care. The key secondary study endpoint of clinical status at Day 15 was also met [63] . In May 2020, National Institute of Allergy and Infectious Diseases completed the phase III ACTT-1 trial (Adaptive COVID-19 Treatment Trial) that evaluated the safety and efficacy of remdesivir for the treatment of COVID-2019 infections (ACTT; 20-0006; U1111-1249-9599; EudraCT2020-001052-18; NCT04280705). The randomised, double-blind, placebo-controlled trial was initiated in February 2020 and enrolled 1062 hospitalised patients in the US, Denmark, Germany, Greece, South Korea, Japan, Mexico, Singapore, Spain and the UK. In April 2020, EvergreenHealth reported initial preliminary reports from the trial. In May 2020, Gilead announced that the trial findings support the use of remdesivir with the largest benefit observed among individuals who required oxygen supplementation but were not mechanically ventilated. In June 2020, the EMA released the efficacy data from the trial [18] [64] [58] [65] . In August 2020, updated results from the trial were released by the company. As of October 2020, Gilead announced that remdesivir significantly improved time to recovery and also reduced the likelihood of disease progression [26] [7] .
In May 2020, NIAID initiated the phase III trial to evaluate the safety and efficacy of remdesivir in combination with oral baricitinib, for the treatment of COVID-19 infections (20-0006 ACTT-II; NCT04401579). The randomised, blinded, controlled trial intends to enrol 1032 patients in the US, Japan, South Korea, Mexico and Singapore [66] [67] [68] .
In April 2020, Capital Medical University, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital and Gilead Sciences suspended the randomised, controlled, double blind phase III CAP-China remdesivir 1 trial, as the epidemic of COVID-2019 was well-controlled, and no eligible patients could be recruited further (NCT04252664). The trial evaluated the efficacy and safety of remdesivir in patients hospitalised with mild or moderate COVID-2019 infections. Patients were randomised 1:1:1 to receive up to 5 days or 10 days of remdesivir with standard of care or standard of care alone. The trial was initiated in February 2020 and enrolled 584 patients in China [69] . In October 2020, Gilead Sciences presented the results of this trial at the IDWeek 2020 (IDW-2020) [70] [71] .
In July 2020, Gilead Sciences initiated a phase II/III CARAVAN trial to evaluate the safety, tolerability, and pharmacokinetics of remdesivir in patients with COVID-19 infections (P201-2020; GS-US540-5823; EudraCT2020-001803-17; NCT04431453). The open-label trial intends to enrol approximately 52 patients, aged 0 to 18 years, in the US, the UK, Italy and Spain [72] .
In August 2020, QuantumLeap Healthcare Collaborative initiated phase II I-SPY-COVID trial to evaluate efficacy of remdesivir in combination with cenicriviroc [see Adis Insight Drug profile800043325], icatibant [see Adis Insight Drug profile800001708], razuprotafib [see Adis Insight Drug profile800035272] and apremilast [see Adis Insight Drug profile800019919] in patients with acute respiratory distress syndrome associated with COVID-19 infections (NCT04488081). An open label, randomised trial intends to enrol 1500 patients in the US [73] . Company announced the enrollment of the first patient in the trial [74] .
In October 2020, BioSig Technologies and ViralClear Pharmaceuticals announced that it has stopped enrollments and halted the phase II trial that designed to evaluate the efficacy and safety of merimepodib [see Adis Insight Drug profile 800008158] in combination with remdesivir in patients with COVID-19 infections (VC02-01; NCT04410354). The double blind, randomised, placebo-controlled trial was initiated in June 2020 in USA. The recent results showed the trial would not meet its primary safety endpoints [75] . In September 2020, ViralClear Pharmaceuticals expanded the size of the trial from 40 to 80 hospitalised COVID-19 patients, and that limited enrollment to seriously ill patients, (NIAID Grade 3, who required high flow, high concentration oxygen to maintain adequate oxygenation). At the time review of the data by the SMC, 44 patients had been enrolled in the trial of whom 42 had received study drug (either merimepodib solution or matching placebo). The most recent review of the data documented all 22 Grade 4 patients were discharged from the hospital and did not relapse during the 37 day follow-up period. However, patients who were NIAID Grade 3 patients (n = 20) at the time of enrollment had markedly different outcomes. Specifically, the unblinded SMC detected an imbalance in survival rates in these NIAID Grade 3 patients between the placebo and merimepodib making it unlikely that the trial would meet its primary safety endpoints. The company has therefore elected to stop enrollment into the clinical trial. Patients will be followed as per the protocol for safety monitoring; however, no further study drug treatments will be administered. The first patient was dosed in June 2020 [76] [77] .
In September 2020, Gilead Sciences initiated a phase I/II trial to evaluate the safety, efficacy, and pharmacokinetics of remdesivir administered by inhalation for early stage COVID-2019 infections (NCT04539262; GS-US-553-9020). The ramdomised study is designed to enroll 282 patients in the US [78] .
In February 2020, Gilead Sciences reported that remdesivir was purportedly used in treating the first case of 2019 novel coronavirus (2019-nCoV), in the US. There was no data for remdesivir displaying activity against 2019-nCoV, but data was available for other coronaviruses [79]
In vitro testing conducted by Gilead has demonstrated that remdesivir is active against the virus that causes COVID-19 [57] .
Inhalation (nanopartical formulation)
In July 2020, NeuroActiva initiated the phase I NEUROSIVIR trial to evaluate the safety, tolerability and pharmacokinetics of inhaled nanoparticle formulation of remdesivir alone and in combination with traneurocin [see Adis Insight Drug Profile 800051889] in healthy adults (NCT04480333). The randomised, placebo controlled trial intends to enrol approximately 48 volunteers in the US [80] .
Compassionate use
In May 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency's (EMA) recommended expanding the compassionate use of remdesivir for the treatment of patients with COVID-2019 infections. The compassionate use recommendations covered the treatment of hospitalised patients requiring supplemental oxygen, non-invasive ventilation, high-flow oxygen devices or ECMO (extracorporeal membrane oxygenation) [81] .
In April 2020, EMA’s human medicines committee (CHMP) gave recommendations for the compassionate use programmes of remdesivir for treatment of coronavirus infections (COVID-19) in the European Union. earlier, Estonia, Greece, the Netherlands and Romania requested an opinion from the CHMP on the conditions for early access to remdesivir through compassionate use could be given to patients with COVID‑19 [82] .
Remdesivir is available through an expanded access programme conducted by U.S. Army Medical Research and Development Command for the treatment of COVID-2019 infections in the US (S-20-01; NCT04302766) [83] .
Gilead Sciences provided remdesivir for compassionate use to 2 patients, one a female patient in the Royal Free Hospital in London in October and one in Guinea the following month [84] .
Gilead Sciences is also providing remdesivir for compassionate use to patients with COVID-2019 infections for emergency treatment outside of ongoing clinical studies [61] .
In July 2020, Gilead Sciences released efficacy and safety data of remdesivir from compassionate use programme for COVID-2019 infections in pediatric patients and in pregnant and postpartum women [55] . In April 2020, Gilead Sciences released efficacy and safety data of remdesivir from compassionate use programme for COVID-2019 infections [85] [86] . Gilead Sciences in April 2020, reported that intravenous infusion of remdesivir demonstrated clinical improvement in first 53 patients who received treatment in compassionate programme [48] .
Ebola virus infections
In August 2019, based on independent Data and Safety Monitoring Board’s (DSMB) recommendation, Gilead Sciences, Ridgeback Biotherapeutics and National Institute of Allergy and Infectious Diseases prematurely prematurely terminated the phase II/III PALM trial designed to assess the safety and effectiveness of mAb 114; REGN 3470/3471/3479 , porgaviximab and remdesivir separately in patients with Ebola virus infections (19-I-0003; NCT03719586). The open-label, randomised, controlled study was initiated in October 2018, and enrolled 1 044 patients in the US and Congo [87] [88] .
In October 2019, National Institute of Allergy and Infectious Diseases completed the phase II PREVAIL IV trial to assess the antiviral activity, safety and tolerability of remdesivir 100mg IV in male Ebola survivors with evidence of Ebola virus persistence (999916137; 16-I-N137; NCT02818582). The randomised 1:1, double-blind, parallel, placebo-controlled, two-phase (treatment and longer-term follow-up) trial was initiated in June 2016 and enrol approximately 30 patients in the Guinea and Liberia. Longer-term clearance of Ebola virus will be assessed during the 5-month follow-up phase [89] .
Gilead initiated a phase I trial in healthy volunteers to evaluate the safety, tolerability and pharmacokinetics of remdesivir [90] .
Preclinical studies
In a monkey model of Ebola virus infections, remdesivir displayed efficacy as well as potential for broad-spectrum anti-filovirus activity with 100% survival of monkeys [91] .
Remdesivir has a broad-spectrum antiviral activity both in vitro and in vivo in animal models against multiple viral pathogens, including Ebola, Marburg, MERS, SARS and SARS-CoV-2 [57] [7] .
Supply arrangement
In July 2020, Gilead Sciences entered into an agreement with U.S. Department of Health and Human Services (HHS) to manage the allocation of remdesivir to hospitals until the end of September [92] .
In October 2020, Gilead Sciences signed a joint procurement agreement (JPA) that will enable rapid and equitable access to remdesivir (Veklury®) for the treatment of COVID-19 in the European Union (EU). The JPA enables participating countries in the EU and the European Economic Area (EEA) and the United Kingdom to purchase remdesivir for both real-time demand and stockpiling needs, coordinated by the European Commission. The agreement covers purchases of remdesivir over the next six months and has the option to be extended [93] .
In July 2020, Gilead entered into an agreement with the European Commission to enable the European Commission to secure treatment doses of remdesivir (Veklury) in order to meet immediate needs. The drug will be made available in the member states and the UK from early August [94] .
Financial information
In July 2020, The emergency authorization of remdesivir received $US6.5 billion in NIH funding for the treatment of COVID-19 infection [95] .
