COVID-19 drug development

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COVID-19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID-19). From early 2020 through 2021, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of preclinical or clinical research (506 total candidates in April 2021), with 419 potential COVID-19 drugs in clinical trials, as of April 2021. [1]

Contents

As early as March 2020, the World Health Organization (WHO), [2] European Medicines Agency (EMA), [3] US Food and Drug Administration (FDA), [4] and the Chinese government and drug manufacturers [5] [6] were coordinating with academic and industry researchers to speed development of vaccines, antiviral drugs, and post-infection therapies. [7] [8] [9] [10] The International Clinical Trials Registry Platform of the WHO recorded 536 clinical studies to develop post-infection therapies for COVID-19 infections, [11] [12] with numerous established antiviral compounds for treating other infections under clinical research to be repurposed. [7] [13] [14] [15]

In March 2020, the WHO initiated the "SOLIDARITY Trial" in 10 countries, enrolling thousands of people infected with COVID-19 to assess treatment effects of four existing antiviral compounds with the most promise of efficacy. [2] [16] A dynamic, systematic review was established in April 2020 to track the progress of registered clinical trials for COVID-19 vaccine and therapeutic drug candidates. [12]

Drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound. [17] Several national regulatory agencies, such as the EMA and the FDA, approved procedures to expedite clinical testing. [4] [18] By June 2021, dozens of potential post-infection therapies were in the final stage of human testing – Phase III–IV clinical trials. [19] An effective, convenient COVID-19 treatment could reach annual sales of over $10 billion, according to a recent Jefferies & Co estimate. [20]

Background

Drug discovery cycle.svg

Drug development is the process of bringing a new infectious disease vaccine or therapeutic drug to the market once a lead compound has been identified through the process of drug discovery. [17] It includes laboratory research on microorganisms and animals, filing for regulatory status, such as via the FDA, for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug. [21] [22] The entire process – from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials – to approved vaccine or drug normally takes more than a decade. [17] [21] [22]

The term "preclinical research" is defined by laboratory studies in vitro and in vivo , indicating a beginning stage for development of a preventative vaccine, antiviral or other post-infection therapies, [7] such as experiments to determine effective doses and toxicity in animals, before a candidate compound is advanced for safety and efficacy evaluation in humans. [23] To complete the preclinical stage of drug development – then be tested for safety and efficacy in an adequate number of people infected with COVID-19 (hundreds to thousands in different countries) – is a process likely to require 1–2 years for COVID-19 therapies, according to several reports in early 2020. [9] [24] [25] [26] Despite these efforts, the success rate for drug candidates to reach eventual regulatory approval through the entire drug development process for treating infectious diseases is only 19%. [27]

Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials – following success in Phase I – evaluate therapeutic efficacy against the COVID-19 disease at ascending dose levels (efficacy based on biomarkers), while closely evaluating possible adverse effects of the candidate therapy (or combined therapies), typically in hundreds of people. A common trial design for Phase II studies of possible COVID-19 drugs is randomized, placebo-controlled, blinded, and conducted at multiple sites, while determining more precise, effective doses and monitoring for adverse effects. [28]

The success rate for Phase II trials to advance to Phase III (for all diseases) is about 31%, and for infectious diseases specifically, about 43%. [27] Depending on its duration (longer more expensive) – typically a period of several months to two years [28] – an average-length Phase II trial costs US$57 million (2013 dollars, including preclinical and Phase I costs). [29] Successful completion of a Phase II trial does not reliably forecast that a candidate drug will be successful in Phase III research. [30]

Phase III trials for COVID-19 involve hundreds-to-thousands of hospitalized participants, and test effectiveness of the treatment to reduce effects of the disease, while monitoring for adverse effects at the optimal dose, such as in the multinational Solidarity and Discovery trials. [2] [17] [31]

Candidates

Evidence network of COVID-19 clinical trials of 15 therapeutic candidates. Circles represent interventions or intervention groups (categories). Lines between two circles indicate comparisons in clinical trials. Real-time dashboard of clinical trials for COVID-19 Lancet avril 2020.jpg
Evidence network of COVID-19 clinical trials of 15 therapeutic candidates. Circles represent interventions or intervention groups (categories). Lines between two circles indicate comparisons in clinical trials.

According to one source (as of August 2020), diverse categories of preclinical or early-stage clinical research for developing COVID-19 therapeutic candidates included: [19]

Pivotal Phase III trials assess whether a candidate drug has efficacy specifically against a disease, and – in the case of people hospitalized with severe COVID-19 infections – test for an effective dose level of the repurposed or new drug candidate to improve the illness (primarily pneumonia) from COVID-19 infection. [2] [11] [33] For an already-approved drug (such as hydroxychloroquine for malaria), Phase III–IV trials determine in hundreds to thousands of COVID-19-infected people the possible extended use of an already-approved drug for treating COVID-19 infection. [33] As of August 2020, over 500 candidate therapeutics were in preclinical or a stage of Phase I–IV development, with new Phase II–III trials announced for hundreds of therapeutic candidates during 2020. [19]

Numerous candidate drugs under study as "supportive" treatments to relieve discomfort during illness, such as NSAIDs or bronchodilators, are not included in the table below. Others in early-stage Phase II trials or numerous treatment candidates in Phase I trials, [19] are also excluded. Drug candidates in Phase I–II trials have a low rate of success (under 12%) to pass through all trial phases to gain eventual approval. [21] [30] Once having reached Phase III trials, therapeutic candidates for diseases related to COVID-19 infection – infectious and respiratory diseases – have a success rate of about 72%. [27]

COVID-19: candidate drug treatments in Phase III–IV trials
Drug candidateDescriptionExisting disease approvalTrial sponsor(s)Location(s)Expected resultsNotes,
references
Remdesivir antiviral; adenosine nucleotide analog inhibiting RNA synthesis in coronaviruses investigational [34] Gilead, WHO, INSERM, NIAIDChina, Japan initially; extended internationally in Global Solidarity and Discovery Trials, and US NIAID ACTT TrialMid-2020 (Chinese, Japanese trials) [19] [35] [36] selectively provided by Gilead for COVID-19 emergency access; [37] [38] both promising and negative effects reported in April [39] [40] [41]
Hydroxychloroquine or chloroquine antiparasitic and antirheumatic; generic made by many manufacturers malaria, rheumatoid arthritis, lupus (International) [42] [43] CEPI, WHO, INSERMMultiple sites in China; global Solidarity and Discovery TrialsJune 2020 (discontinued by WHO) multiple side effects; possible adverse prescription drug interactions; [42] [43] discontinued in June from WHO Solidarity trial and UK Recovery trial as "having no clinical benefit in hospitalised patients with COVID-19"; [44] [45] trials [19] [35]
Favipiravir antiviral against influenzainfluenza (China) [46] Fujifilm ChinaApril 2020 [19] [8] [47]
Lopinavir/ritonavir without or with interferon beta-1a antiviral, immune suppressioninvestigational combination; lopinavir/ritonavir approved [48] CEPI, WHO, UK Government, Univ. of Oxford, INSERMGlobal Solidarity and Discovery Trials, multiple countriesmid-2020 [19] [35]
Sarilumab human monoclonal antibody against interleukin-6 receptor rheumatoid arthritis (US, Europe) [49] Regeneron-Sanofi Multiple countriesSpring 2020 [19] [50]
ASC-09 + ritonavir antiviralcombination not approved; ritonavir approved for HIV [48] Ascletis PharmaMultiple sites in ChinaSpring 2020 [19] [51]
Tocilizumab human monoclonal antibody against interleukin-6 receptorimmunosuppression, rheumatoid arthritis (US, Europe) [52] Genentech-Hoffmann-La Roche Multiple countriesmid-2020 [19] [53] Roche announced in late July that its Phase III trial of tocilizumab for treating pneumonia in hospitalized people with COVID-19 infection was ineffective [54]
Lenzilumab humanized monoclonal antibody for relieving pneumonianew drug candidateHumanigen, Inc.Multiple sites in the United StatesSeptember 2020 [19] [55]
Dapagliflozin sodium-glucose cotransporter 2 inhibitor hypoglycemia agent [56] Saint Luke's Mid America Heart Institute, AstraZeneca Multiple countriesDecember 2020 [19] [57]
CD24Fcantiviral immunomodulator against inflammatory responsenew drug candidateOncoImmune, Inc.Multiple sites in the United States2021 [19] [58]
Apabetaloneselective BET inhibitorinvestigationalResverlogix CorpUnited States22 March 2022 [19] [59]

Repurposed drug candidates

Drug repositioning (also called drug repurposing) – the investigation of existing drugs for new therapeutic purposes – is one line of scientific research followed to develop safe and effective COVID-19 treatments. [15] [60] Several existing antiviral medications, previously developed or used as treatments for Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV/AIDS, and malaria, are being researched as COVID-19 treatments, with some moving into clinical trials. [13]

During the COVID-19 pandemic, drug repurposing is the clinical research process of rapidly screening and defining the safety and efficacy of existing drugs already approved for other diseases to be used for people with COVID-19 infection. [13] [15] [61] In the usual drug development process, [17] confirmation of repurposing for new disease treatment would take many years of clinical research – including pivotal Phase III clinical trials – on the candidate drug to assure its safety and efficacy specifically for treating COVID-19 infection. [13] [61] In the emergency of a growing COVID-19 pandemic, the drug repurposing process was being accelerated during March 2020 to treat people hospitalized with COVID-19. [2] [13] [15]

Clinical trials using repurposed, generally safe, existing drugs for hospitalized COVID-19 people may take less time and have lower overall costs to obtain endpoints proving safety (absence of serious side effects) and post-infection efficacy, and can rapidly access existing drug supply chains for manufacturing and worldwide distribution. [2] [13] [62] In an international effort to capture these advantages, the WHO began in mid-March 2020 expedited international Phase II–III trials on four promising treatment options – the SOLIDARITY trial [2] [63] [64] – with numerous other drugs having potential for repurposing in different disease treatment strategies, such as anti-inflammatory, corticosteroid, antibody, immune, and growth factor therapies, among others, being advanced into Phase II or III trials during 2020. [19] [13] [61] [65]

In March, the United States Centers for Disease Control and Prevention (CDC) issued a physician advisory concerning remdesivir for people hospitalized with pneumonia caused by COVID-19: "While clinical trials are critical to establish the safety and efficacy of this drug, clinicians without access to a clinical trial may request remdesivir for compassionate use through the manufacturer for patients with clinical pneumonia." [38]

Novel antibody drugs

Convalescent plasma

Convalescent plasma collected at a blood donor center during the COVID-19 pandemic. Convalescent plasma collected during COVID-19 pandemic.jpg
Convalescent plasma collected at a blood donor center during the COVID-19 pandemic.

Passive immunization with convalescent plasma or hyperimmune serum has been proposed as a potential treatment for COVID-19. [66] [ needs update ]

In the United States, the FDA has granted temporary authorization to convalescent plasma (plasma from the blood of people who have recovered from COVID-19, which thus contains antibodies against SARS-CoV-2) as an experimental treatment in cases where the person's life is seriously or immediately threatened. [67] However, convalescent plasma treatment has not undergone the randomized controlled or non-randomized clinical studies needed to determine if is safe and effective for treating people with COVID-19. [66] [68] [69]

Argentina, Brazil, Costa Rica, and Mexico have pursued development of antisera. [70] Brazil began development of an equine hyperimmune serum, obtained by inoculating horses with recombinant SARS-CoV-2 spike protein, in mid-2020. A consortium of Instituto Vital Brazil, UFRJ, the Oswaldo Cruz Foundation and the D’Or Institute for Research and Education in Rio de Janeiro began preclinical trials in May 2020, [71] while Instituto Butantan in São Paulo completed animal testing in September. [70] In December 2020, Argentina granted emergency authorization to CoviFab, a locally developed formulation of equine hyperimmune serum, for use in cases of moderate to severe COVID-19, based on the initial results of a single phase 2/3 trial which suggested reductions in mortality, ICU admission, and mechanical ventilation requirements in patients who received the serum. [72] [73] This was harshly criticized by the Argentine Intensive Care Society, which stated that the trial failed to achieve its primary or secondary endpoints and did not demonstrate any statistically significant differences between the serum and placebo groups. [73]

Casirivimab/imdevimab

REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB: 6VSB, 6XDG . REGN-COV2 binding SARS-CoV-2 spike protein.png
REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB: 6VSB, 6XDG .

Casirivimab/imdevimab, sold under the brand name REGEN-COV among others, [74] is a medicine developed by the American biotechnology company Regeneron Pharmaceuticals. It is an artificial "antibody cocktail" designed to produce resistance against the SARS-CoV-2 coronavirus responsible for the COVID-19 pandemic. [75] [76] It consists of two monoclonal antibodies, casirivimab (REGN10933) and imdevimab (REGN10987) that must be mixed together. [74] [77] [78] The combination of two antibodies is intended to prevent mutational escape. [79] It is also available as a co-formulated product. [80]

The combination was approved under the brand name Ronapreve for medical use in Japan, in the UK, and in other countries. [81] [82] [83] [84] [85]

Bamlanivimab and etesevimab

Bamlanivimab/etesevimab is a combination of two monoclonal antibodies, bamlanivimab and etesevimab, administered together via intravenous infusion as a treatment for COVID-19. [86] [87] [88] [89] Both types of antibody target the surface spike protein of SARS‑CoV‑2. [90] [91]

Bamlanivimab and etesevimab, administered together, are authorized in the United States for the treatment of mild-to-moderate COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. [92] [93] They are also authorized, when administered together, for use after exposure to the SARS-CoV-2 virus for post-exposure prophylaxis (prevention) for COVID-19 and are not authorized for pre-exposure prophylaxis to prevent COVID-19 before being exposed to the SARS-CoV-2 virus. [92] [93]

Sotrovimab

In May 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) concluded that sotrovimab can be used to treat confirmed COVID-19 in people aged twelve years and older, weighing at least 40 kilograms (88 lb), who do not require supplemental oxygen therapy, and who are at risk of progressing to severe COVID-19. [94]

In May 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for sotrovimab for the treatment of mild-to-moderate COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19, including hospitalization or death. [95] [96] [97] [98]

In August 2021, it was granted provisional approval for the treatment of COVID-19 in Australia. [99]

Tixagevimab/cilgavimab

Tixagevimab/cilgavimab is a combination of two human monoclonal antibodies, tixagevimab (AZD8895) and cilgavimab (AZD1061), under investigation as a treatment for COVID-19. It is being developed by British-Swedish multinational pharmaceutical and biotechnology company AstraZeneca. [100] [101]

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of tixagevimab/cilgavimab, which is being developed by AstraZeneca AB, for the prevention of COVID-19 in adults. [102]

In October 2021, AstraZeneca requested Emergency Use Authorization for tixagevimab/cilgavimab to prevent COVID-19 from the U.S. Food and Drug Administration (FDA). [103] [104]

Regdanvimab

Regdanvimab is a human monoclonal antibody under investigation for the treatment of COVID-19. [105] [106] [107] Celltrion develops the treatment. The antibody is directed against the spike protein of SARS-CoV-2

In March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of data on regdanvimab. [105] [108] In October 2021, the EMA started evaluating an application for marketing authorization for the monoclonal antibody regdanvimab (Regkirona) to treat adults with COVID-19 who do not require supplemental oxygen therapy and who are at increased risk of progressing to severe COVID 19. [109] The applicant is Celltrion Healthcare Hungary Kft. [109]

The European Medicines Agency (EMA) concluded that regdanvimab can be used for the treatment of confirmed COVID-19 in adults who do not require supplemental oxygen therapy and who are at high risk of progressing to severe COVID-19. [110] The medicine is given by infusion (drip) into a vein. [110]

Novel viral replication inhibitors

Molnupiravir

MK-4482.svg

Molnupiravir, sold under the brand name Lagevrio, is an antiviral medication that inhibits the replication of certain RNA viruses, and is used to treat COVID-19 in those infected by SARS-CoV-2. [111]

Molnupiravir is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine (also called EIDD-1931), and exerts its antiviral action through introduction of copying errors during viral RNA replication. [112] [113]

Molnupiravir was originally developed to treat influenza at Emory University by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE). It was then acquired by Miami-based company Ridgeback Biotherapeutics, which later partnered with Merck & Co. to develop the drug further. [114]

Molnupiravir was approved for medical use in the United Kingdom in November 2021. [115] [116]

Novel protease inhibitors

PF-07321332

Xray crystal (PDB:7SI9 and 7VH8) of the structure SARS-CoV-2 protease inhibitor PF-07321332 bound the viral 3CLpro (Mpro) protease enzyme. Ribbon diagram of the protein with the drug shown as sticks. The catalytic residues (His41, Cys145) are shown as yellow sticks. Xray crystal structure PDB-7si9.png
Xray crystal (PDB:7SI9 and 7VH8) of the structure SARS-CoV-2 protease inhibitor PF-07321332 bound the viral 3CLpro (Mpro) protease enzyme. Ribbon diagram of the protein with the drug shown as sticks. The catalytic residues (His41, Cys145) are shown as yellow sticks.

PF-07321332 is an antiviral drug developed by Pfizer which acts as an orally active 3CL protease inhibitor. It is a covalent inhibitor, binding directly to the catalytic cysteine (Cys145) residue of the enzyme.

PF-07321332 is in phase III trials for the treatment of COVID-19 in combination with ritonavir. [117] [118] [119] [120] [121] [122] In this combination, ritonavir serves to slow down metabolism of PF-07321332 by cytochrome enzymes to maintain higher circulating concentrations of the main drug. [123] In November 2021, Pfizer announced positive phase 2/3 results, including 89% reduction in hospitalizations when given within three days after symptom onset. [124] Despite not being fully approved yet in either country, The UK has begun stockpiling PF-07321332, [125] and Australia has preordered 500,000 courses of the drug. [126]

Planning and coordination

Early planning

Over 2018–20, new initiatives to stimulate vaccine and antiviral drug development included partnerships between governmental organizations and industry, such as the European Innovative Medicines Initiative, [127] the US Critical Path Initiative to enhance innovation of drug development, [128] and the Breakthrough Therapy designation to expedite development and regulatory review of promising candidate drugs. [129] To accelerate refinement of diagnostics for detecting COVID-19 infection, a global diagnostic pipeline tracker was formed. [130]

According to a tracker of clinical trial progress on potential therapeutic drugs for COVID-19 infections, 29 Phase II–IV efficacy trials were concluded in March 2020 or scheduled to provide results in April from hospitals in China – which experienced the first outbreak of COVID-19 in late 2019. [19] Seven trials were evaluating repurposed drugs already approved to treat malaria, including four studies on hydroxychloroquine or chloroquine phosphate. [19] Repurposed antiviral drugs make up most of the Chinese research, with 9 Phase III trials on remdesivir across several countries due to report by the end of April. [19] Other potential therapeutic candidates under pivotal clinical trials concluding in March–April are vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2, among others.

The COVID-19 Clinical Research Coalition has goals to 1) facilitate rapid reviews of clinical trial proposals by ethics committees and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data, and 4) facilitate sharing of clinical trial outcomes before publication. [11] A dynamic review of clinical development for COVID-19 vaccine and drug candidates was in place, as of April. [12]

By March 2020, the international Coalition for Epidemic Preparedness Innovations (CEPI) committed to research investments of US$100 million across several countries, [131] and issued an urgent call to raise and rapidly invest $2 billion for vaccine development. [132] Led by the Bill and Melinda Gates Foundation with partners investing US$125 million and coordinating with the World Health Organization, the COVID-19 Therapeutics Accelerator began in March, facilitating drug development researchers to rapidly identify, assess, develop, and scale up potential treatments. [133] The COVID-19 Clinical Research Coalition formed to coordinate and expedite results from international clinical trials on the most promising post-infection treatments. [11] In early 2020, numerous established antiviral compounds for treating other infections were being repurposed or developed in new clinical research efforts to alleviate the illness of COVID-19. [7] [13] [19]

During March 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) initiated an international COVID-19 vaccine development fund, with the goal to raise US$2 billion for vaccine research and development, [134] and committed to investments of US$100 million in vaccine development across several countries. [131] The Canadian government announced CA$275 million in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian universities, [135] [136] with plans to establish a "vaccine bank" of new vaccines for implementation if another COVID-19 outbreak occurs. [136] [137] The Bill & Melinda Gates Foundation invested US$150 million in April for development of COVID-19 vaccines, diagnostics, and therapeutics. [138]

Computer-assisted research

In March 2020, the United States Department of Energy, National Science Foundation, NASA, industry, and nine universities pooled resources to access supercomputers from IBM, combined with cloud computing resources from Hewlett Packard Enterprise, Amazon, Microsoft, and Google, for drug discovery. [139] [140] The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy. [139] [140]

The C3.ai Digital Transformation Institute, an additional consortium of Microsoft, six universities (including the Massachusetts Institute of Technology, a member of the first consortium), and the National Center for Supercomputer Applications in Illinois, working under the auspices of C3.ai, an artificial intelligence software company, are pooling supercomputer resources toward drug discovery, medical protocol development and public health strategy improvement, as well as awarding large grants to researchers who proposed by May to use AI to carry out similar tasks. [141] [142]

In March 2020, the distributed computing project Folding@home launched a program to assist drug developers, initially simulating protein targets from SARS-CoV-2 and the related SARS-CoV virus, which has been studied previously. [143] [144] [145]

Distributed computing project Rosetta@home also joined the effort in March. The project uses computers of volunteers to model SARS-CoV-2 virus proteins to discover possible drug targets or create new proteins to neutralize the virus. Researchers revealed that with the help of Rosetta@home, they had been able to “accurately predict the atomic-scale structure of an important coronavirus protein weeks before it could be measured in the lab.” [146]

In May 2020, the OpenPandemics – COVID-19 partnership between Scripps Research and IBM's World Community Grid was launched. The partnership is a distributed computing project that "will automatically run a simulated experiment in the background [of connected home PCs] which will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19". [147]

International Solidarity and Discovery Trials

In March, the World Health Organization (WHO) launched the coordinated "Solidarity Trial" in 10 countries on five continents to rapidly assess in thousands of COVID-19 infected people the potential efficacy of existing antiviral and anti-inflammatory agents not yet evaluated specifically for COVID-19 illness. [2] [16] By late April, hospitals in over 100 countries were involved in the trial. [148]

The individual or combined drugs undergoing initial studied are 1) lopinavirritonavir combined, 2) lopinavir–ritonavir combined with interferon-beta, 3) remdesivir or 4) (hydroxy)chloroquine in separate trials and hospital sites internationally. [2] [16] Following a study published by The Lancet on safety concerns with hydroxychloroquine, the WHO suspended use of it from the Solidarity trial in May 2020, [149] [150] reinstated it after the research was retracted, [151] then abandoned further use of the drug for COVID-19 treatment when analysis showed in June that it provided no benefit. [44]

With about 15% of people infected by COVID-19 having severe illness, and hospitals being overwhelmed during the pandemic, WHO recognized a rapid clinical need to test and repurpose these drugs as agents already approved for other diseases and recognized as safe. [2] The Solidarity project is designed to give rapid insights to key clinical questions: [2] [152]

Enrolling people with COVID-19 infection is simplified by using data entries, including informed consent, on a WHO website. After the trial staff determines the drugs available at the hospital, the WHO website randomizes the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the WHO Solidarity website. The design of the Solidarity trial is not double-blind – which is normally the standard in a high-quality clinical trial – but the WHO needed speed with quality for the trial across many hospitals and countries. [2] A global safety monitoring board of WHO physicians examine interim results to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy. [2] [152] A similar web-based study to Solidarity, called "Discovery", was initiated in March across seven countries by INSERM (Paris, France). [2] [35]

The Solidarity trial seeks to implement coordination across hundreds of hospital sites in different countries – including those with poorly-developed infrastructure for clinical trials – yet needs to be conducted rapidly. According to John-Arne Røttingen, chief executive of the Research Council of Norway and chairman of the Solidarity trial international steering committee, the trial would be considered effective if therapies are determined to "reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems." [31]

During March, funding for the Solidarity trial reached US$108 million from 203,000 individuals, organizations and governments, with 45 countries involved in financing or trial management. [149]

A clinical trial design in progress may be modified as an "adaptive design" if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment. [153] [154] The global Solidarity and European Discovery trials of hospitalized people with severe COVID-19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge. [11] [35] [155] Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations. [30] [154] [156]

Adaptive COVID-19 Treatment Trial

The US National Institute of Allergy and Infectious Diseases (NIAID) initiated an adaptive design, international Phase III trial (called "ACTT") to involve up to 800 hospitalized COVID-19 people at 100 sites in multiple countries. Beginning with use of remdesivir as the primary treatment over 29 days, the trial definition of its adaptive protocol states that "there will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s)." [39]

Operation Warp Speed

Official seal of Operation Warp Speed Operation Warp Speed.png
Official seal of Operation Warp Speed

Operation Warp Speed (OWS) was a public–private partnership initiated by the United States government to facilitate and accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. [157] [158] The first news report of Operation Warp Speed was on April 29, 2020, [159] [160] [161] and the program was officially announced on May 15, 2020. [157] It was headed by Moncef Slaoui from May 2020 to January 2021 and by David A. Kessler from January to February 2021. [162] At the end of February 2021, Operation Warp Speed was transferred into the responsibilities of the White House COVID-19 Response Team. [163]

The program promoted mass production of multiple vaccines, and different types of vaccine technologies, based on preliminary evidence, allowing for faster distribution if clinical trials confirm one of the vaccines is safe and effective. The plan anticipated that some of these vaccines will not prove safe or effective, making the program more costly than typical vaccine development, but potentially leading to the availability of a viable vaccine several months earlier than typical timelines. [164]

Operation Warp Speed, initially funded with about $10 billion from the CARES Act (Coronavirus Aid, Relief, and Economic Security) passed by the United States Congress on March 27, [157] was an interagency program that includes components of the Department of Health and Human Services, including the Centers for Disease Control and Prevention, Food and Drug Administration, the National Institutes of Health, and the Biomedical Advanced Research and Development Authority (BARDA); the Department of Defense; private firms; and other federal agencies, including the Department of Agriculture, the Department of Energy, and the Department of Veterans Affairs. [157]

RECOVERY Trial

A large-scale, randomized controlled trial named the RECOVERY Trial was set up in March 2020, in the UK to test possible treatments for COVID-19. It is run by the Nuffield Departments of Public Health and of Medicine at the University of Oxford and is testing five repurposed drugs and also convalescent plasma. The trial enrolled more than 11,500 COVID-19 positive participants in the U.K by June 2020. [45] [165] [166]

During April, the British RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was launched initially in 132 hospitals across the UK, [167] expanding to become one of the world's largest COVID-19 clinical studies, involving 5400 infected people under treatment at 165 UK hospitals, as of mid-April. [168] The trial is examining different potential therapies for severe COVID-19 infection: lopinavir/ritonavir, low-dose dexamethasone (an anti-inflammatory steroid), hydroxychloroquine, and azithromycin (a common antibiotic). [165] In June, the trial arm using hydroxychloroquine was discontinued when analyses showed it provided no benefit. [45]

On 16 June the trial group released a statement that dexamethasone had been shown to reduce mortality in patients receiving respiratory support. [169] In a controlled trial around 2,000 hospital patients were given dexamethasone and were compared with more than 4,000 who did not receive the drug. For patients on ventilators, it cut the risk of death from 40% to 28% (1 in 8). For patients needing oxygen, it cut the risk of death from 25% to 20% (1 in 5). [170]

By the end of June 2020, the trial had published findings regarding hydroxychloroquine and dexamethasone. [45] [171] It had also announced results for lopinavir/ritonavir which were published in October 2020. The lopinavir-ritonavir and hydroxychloroquine arms were closed to new entrants after being shown to be ineffective. [45] [172] [173] Dexamethasone was closed to new adult entries after positive results and by November 2020, was open to child entries.

See also

Related Research Articles

Drug development

Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug. The entire process – from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials – to approved vaccine or drug typically takes more than a decade.

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis, a severe form of arthritis in children. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.

Tonix Pharmaceuticals is a pharmaceutical company based in Chatham, New jersey that focuses on repurposed drugs for central nervous system conditions and as of 2020 was also pursuing a vaccine for COVID-19 and a biodefense project.

Remdesivir Antiviral drug

Remdesivir, sold under the brand name Veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. It is administered via injection into a vein. During the COVID-19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID‑19 in around 50 countries. Updated guidelines from the World Health Organization in November 2020 include a conditional recommendation against the use of remdesivir for the treatment of COVID-19.

Emapalumab, sold under the brand name Gamifant, is an anti-interferon-gamma (IFNγ) antibody medication used for the treatment of hemophagocytic lymphohistiocytosis (HLH), which has no cure.

COVID-19 vaccine Vaccine designed to provide acquired immunity against SARS-CoV-2

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus that causes coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, an established body of knowledge existed about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). This knowledge accelerated the development of various vaccine platforms during early 2020. The initial focus of SARS-CoV-2 vaccines was on preventing symptomatic, often severe illness. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19. The COVID‑19 vaccines are widely credited for their role in reducing the spread, severity, and death caused by COVID-19.

Moderna COVID-19 vaccine RNA COVID-19 vaccine

The Moderna COVID‑19 vaccine, codenamed mRNA-1273 and sold under the brand name Spikevax, is a COVID-19 vaccine developed by American company Moderna, the United States National Institute of Allergy and Infectious Diseases (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA). It is authorized for use in people aged twelve years and older in some jurisdictions and for people eighteen years and older in other jurisdictions to provide protection against COVID-19 which is caused by infection by the SARS-CoV-2 virus. It is designed to be administered as two or three 0.5 mL doses given by intramuscular injection at an interval of at least 28 days apart.

COVID-19 drug repurposing research Drug repurposing research related to COVID-19

Drug repositioning is the repurposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed. This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments. Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.

Solidarity trial Accelerated multinational clinical trial program to identify therapies against COVID-19

The Solidarity trial for treatments is a multinational Phase III-IV clinical trial organized by the World Health Organization (WHO) and partners to compare four untested treatments for hospitalized people with severe COVID-19 illness. The trial was announced 18 March 2020, and as of 6 August 2021, 12,000 patients in 30 countries had been recruited to participate in the trial.

Molnupiravir Antiviral medication

Molnupiravir, sold under the brand name Lagevrio, is an antiviral medication that inhibits the replication of certain RNA viruses, and is used to treat COVID-19 in those infected by SARS-CoV-2.

Jason S. McLellan is a structural biologist, professor in the Department of Molecular Biosciences and Robert A. Welch Chair in Chemistry at The University of Texas at Austin who specializes in understanding the structure and function of viral proteins, including those of coronaviruses. His research focuses on applying structural information to the rational design of vaccines and other therapies for viruses, including SARS-CoV-2, the novel coronavirus that causes COVID-19. McLellan and his team collaborated with researchers at the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center to design a stabilized version of the SARS-CoV-2 spike protein, which biotechnology company Moderna used as the basis for the vaccine mRNA-1273, the first COVID-19 vaccine candidate to enter phase I clinical trials in the U.S. At least three other vaccines use this modified spike protein: those from Pfizer and BioNTech; Johnson & Johnson and Janssen Pharmaceutica; and Novavax.

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus. One year into the pandemic, highly effective vaccines have now been introduced and are beginning to slow the spread of SARS-CoV-2; however, for those awaiting vaccination, as well as for the estimated millions of immunocompromised persons who are unlikely to respond robustly to vaccination, treatment remains important. Thus, the lack of progress developing effective treatments means that the cornerstone of management of COVID-19 has been supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.

Casirivimab/imdevimab Antiviral combination medication

Casirivimab/imdevimab, sold under the brand name REGEN-COV among others, is a medicine developed by the American biotechnology company Regeneron Pharmaceuticals. It is an artificial "antibody cocktail" designed to produce resistance against the SARS-CoV-2 coronavirus responsible for the COVID-19 pandemic. It consists of two monoclonal antibodies, casirivimab (REGN10933) and imdevimab (REGN10987) that must be mixed together. The combination of two antibodies is intended to prevent mutational escape. It is also available as a co-formulated product.

Bamlanivimab is a monoclonal antibody developed by AbCellera Biologics and Eli Lilly as a treatment for COVID-19. The drug was granted an emergency use authorization (EUA) by the US Food and Drug Administration (FDA) in November 2020, and 950,000 doses have been bought by the US government as of December 2020. In April 2021, the EUA was revoked.

ZF2001 Vaccine against COVID-19

ZF2001, trade-named ZIFIVAX or ZF-UZ-VAC-2001, is an adjuvanted protein subunit COVID-19 vaccine developed by Anhui Zhifei Longcom in collaboration with the Institute of Microbiology at the Chinese Academy of Sciences. The vaccine candidate is in Phase III trials with 29,000 participants in China, Ecuador, Malaysia, Pakistan, and Uzbekistan.

History of COVID-19 vaccine development Scientific work to develop a vaccine for COVID-19

COVID-19's caused virus, SARS-CoV-2, was isolated in late 2019. Its genetic sequence was published on 11 January 2020, triggering an urgent international response to prepare for an outbreak and hasten development of a preventive COVID-19 vaccine. Since 2020, vaccine development has been expedited via unprecedented collaboration in the multinational pharmaceutical industry and between governments. By June 2020, tens of billions of dollars were invested by corporations, governments, international health organizations, and university research groups to develop dozens of vaccine candidates and prepare for global vaccination programs to immunize against COVID‑19 infection. According to the Coalition for Epidemic Preparedness Innovations (CEPI), the geographic distribution of COVID‑19 vaccine development shows North American entities to have about 40% of the activity, compared to 30% in Asia and Australia, 26% in Europe, and a few projects in South America and Africa.

Chloroquine and hydroxychloroquine during the COVID-19 pandemic

Chloroquine and hydroxychloroquine are anti-malarial medications also used against some auto-immune diseases. Chloroquine, along with hydroxychloroquine, was an early failed experimental treatment for COVID-19. They are not effective for preventing infection.

Viral vector vaccine Type of vaccine

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material coding for a desired antigen into the recipient's host cells. As of April 2021, six viral vector vaccines have been authorized for use in humans in at least one country: four COVID-19 vaccines and two Ebola vaccines.

Sotrovimab, sold under the brand name Xevudy, is an investigational human neutralizing dual-action monoclonal antibody with activity against severe acute respiratory syndrome coronavirus 2, known as SARS-CoV-2. It is under development by GlaxoSmithKline and Vir Biotechnology, Inc. Sotrovimab is designed to attach to the spike protein of SARS-CoV-2.

COVID-19 vaccine clinical research

COVID-19 vaccine clinical research uses clinical research to establish the characteristics of COVID-19 vaccines. These characteristics include efficacy, effectiveness and safety. 24 vaccines are authorized for use by national governments, including six approved for emergency or full use by at least one WHO-recognised stringent regulatory authority; while five are in Phase IV. 204 vaccines are undergoing clinical trials that have yet to be authorized. Nine clinical trials consider heterologous vaccination courses.

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