COVID-19 drug development

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 over 600 potential therapies for COVID‑19 disease in various stages of preclinical or clinical research,[1] with 391 therapeutic candidates in clinical trials, as of January 2021.[2]

This article is about potential therapeutic drugs for COVID‑19. For a potential COVID‑19 vaccine, see COVID-19 vaccine. For drugs that may be repurposed for treating COVID‑19, see COVID-19 drug repurposing research.

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As early as March 2020, the World Health Organization (WHO),[3] European Medicines Agency (EMA),[4] US Food and Drug Administration (FDA),[5] and the Chinese government and drug manufacturers[6][7] were coordinating with academic and industry researchers to speed development of vaccines, antiviral drugs, and post-infection therapies.[8][9][10][11] The International Clinical Trials Registry Platform of the WHO recorded 536 clinical studies to develop post-infection therapies for COVID‑19 infections,[12][13] with numerous established antiviral compounds for treating other infections under clinical research to be repurposed.[8][14][15][16][17]

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.[3][18] 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.[13]

Drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound.[19] Several national regulatory agencies, such as the EMA and the FDA, approved procedures to expedite clinical testing.[5][20] By January 2021, dozens of potential post-infection therapies were in the final stage of human testing – Phase III–IV clinical trials.[1][2][21]

Process

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.[19] 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.[22][23] 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.[19][22][23]

New chemical entities
Main article: Drug discovery

Development of a COVID‑19 vaccine or therapeutic antiviral drug begins with matching a chemical concept to the potential prophylactic mechanism of the future vaccine or antiviral activity in vivo.[22][23][24]

Timeline showing the various drug approval tracks and research phases[19][22][25]

Drug design and laboratory testing
Main article: Pre-clinical development

New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of drug discovery to specify a vaccine or antiviral therapeutic candidate having promise for activity against a biological target related to COVID‑19 disease.[26] At the beginning of vaccine or drug development, little is known about the safety, toxicity, pharmacokinetics, and metabolism of the NCE in humans.[19][22][23] It is the function and obligation of drug development to assess all of these parameters prior to human clinical trials to prove safety and efficacy. A further major objective of drug development is to recommend the dose and schedule for the first use in a human clinical trial ("first-in-human" [FIH] or First Human Dose [FHD], previously also known as "first-in-man" [FIM]).

In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility. Manufacturers must optimize the process they use to make the chemical so they can scale up from a medicinal chemist producing milligrams, to manufacturing on the kilogram and ton scale.[22][23] They further examine the product for suitability to package as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations. Together, these processes are known in preclinical and clinical development as chemistry, manufacturing, and control (CMC).[22]

Many aspects of drug development focus on satisfying the regulatory requirements of drug licensing authorities.[19] These generally constitute tests designed to determine the major toxicities of a novel compound prior to first use in humans.[19][22] It is a regulatory requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g., the skin if the new vaccine is to be delivered by skin injection). Increasingly, these tests are made using in vitro methods (e.g., with isolated cells), but many tests can only be made by using experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity.[22][27]

The information is gathered from this preclinical testing, as well as information on CMC, and submitted to regulatory authorities (in the US, to the Food and Drug Administration (FDA)), as an Investigational New Drug (IND) or Biologics License Application (BLA) application for a vaccine.[19][22][23][24] If the IND is approved, development moves to the clinical phase,[19] and the progress of performance in humans – if a vaccine under development in the United States – is monitored by the FDA in a "vaccine approval process."[28]

Efforts to streamline drug discovery
See also: Operation Warp Speed

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,[29] the US Critical Path Initiative to enhance innovation of drug development,[30] and the Breakthrough Therapy designation to expedite development and regulatory review of promising candidate drugs.[31] To accelerate refinement of diagnostics for detecting COVID‑19 infection, a global diagnostic pipeline tracker was formed.[32]

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,[33] and committed to investments of US$100 million in vaccine development across several countries.[34] 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,[35][36] with plans to establish a "vaccine bank" of new vaccines for implementation if another coronavirus outbreak occurs.[36][37] The Bill & Melinda Gates Foundation invested US$150 million in April for development of COVID‑19 vaccines, diagnostics, and therapeutics.[38]

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.[39][40] 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.[39][40]

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.[41][42]

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.[43][44][45]

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.”[46]

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".[47]

Clinical trial phases
Main article: Clinical trial

Clinical trial programs involve three, multiple-year stages toward product approval, and a fourth, post-approval stage for ongoing safety monitoring of the vaccine or drug therapy:[19][48]

  • Phase I trials, usually in healthy volunteers, determine safety and dosing.
  • Phase II trials are used to establish an initial reading of efficacy and further explore safety in small numbers of people having the disease targeted by the NCE.
  • Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of people with the COVID‑19 infection. If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the new drug application (NDA) stage to begin marketing.[19]
  • Phase IV trials are post-approval trials that may be a condition attached by the FDA, also called post-market surveillance studies. Until a vaccine is provided to the general population, all potential adverse events remain unidentified, requiring that vaccines undergo Phase IV studies with regular reports by the manufacturer to the Vaccine Adverse Event Reporting System (VAERS) to identify problems after use in the population begins.[28]

The process of defining characteristics of the drug does not stop once an NCE is advanced into human clinical trials. In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others).[22][28] If a vaccine candidate or antiviral compound emerges from these tests with an acceptable toxicity and safety profile, and the manufacturer can further show it has the desired effect in clinical trials, then the NCE portfolio of evidence can be submitted for marketing approval in the various countries where the manufacturer plans to sell it.[19] In the United States, this process is called a "new drug application" or NDA.[19][22]

Adaptive designs for COVID‑19 trials

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.[49][50] 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.[12][51][52] 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.[50][53][54]

Failure rate

Most novel drug candidates (NCEs) fail during drug development, either because they have unacceptable toxicity or because they simply do not prove efficacy on the targeted disease, as shown in Phase II–III clinical trials.[19][22] Critical reviews of drug development programs indicate that Phase II–III clinical trials fail due mainly to unknown toxic side effects (50% failure of Phase II cardiology trials), and because of inadequate financing, trial design weaknesses, or poor trial execution.[53][55]

A study covering clinical research in the 1980–90s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing.[56] During 2006–15, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16% specifically for vaccines.[57] The high failure rates associated with pharmaceutical development are referred to as an "attrition rate", requiring decisions during the early stages of drug development to "kill" projects early to avoid costly failures.[57][58]

Cost
Main article: Cost of drug development

One 2010 study assessed both capitalized and out-of-pocket costs for bringing a single new drug to market as about US$1.8 billion and $870 million, respectively.[59] A median cost estimate of 2015–16 trials for development of 10 anti-cancer drugs was $648 million.[60] In 2017, the median cost of a pivotal trial across all clinical indications was $19 million.[61]

The average cost (2013 dollars) of each stage of clinical research was US$25 million for a Phase I safety study, $59 million for a Phase II randomized controlled efficacy study, and $255 million for a pivotal Phase III trial to demonstrate its equivalence or superiority to an existing approved drug,[62] possibly as high as $345 million.[61] The average cost of conducting a 2015–16 pivotal Phase III trial on an infectious disease drug candidate was $22 million.[61]

The full cost of bringing a new drug (i.e., new chemical entity) to market – from discovery through clinical trials to approval – is complex and controversial.[22][23][61][63] In a 2016 review of 106 drug candidates assessed through clinical trials, the total capital expenditure for a manufacturer having a drug approved through successful Phase III trials was $2.6 billion (in 2013 dollars), an amount increasing at an annual rate of 8.5%.[62] Over 2003–2013 for companies that approved 8–13 drugs, the cost per drug could rise to as high as $5.5 billion, due mainly to international geographic expansion for marketing and ongoing costs for Phase IV trials for continuous safety surveillance.[64]

Alternatives to conventional drug development have the objective for universities, governments, and the pharmaceutical industry to collaborate and optimize resources.[65]

COVID-19 clinical trials overview: timelines in 2020

According to two organizations tracking clinical trial progress on potential therapeutic drugs for COVID‑19 infections, 29 Phase II–IV efficacy trials were concluded in March or scheduled to provide results in April from hospitals in China – which experienced the first outbreak of COVID‑19 in late 2019.[1][21] Seven trials were evaluating repurposed drugs already approved to treat malaria, including four studies on hydroxychloroquine or chloroquine phosphate.[21] 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.[21] 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.[12] A dynamic review of clinical development for COVID‑19 vaccine and drug candidates was in place, as of April.[13]

By March 2020, the international Coalition for Epidemic Preparedness Innovations (CEPI) committed to research investments of US$100 million across several countries,[34] and issued an urgent call to raise and rapidly invest $2 billion for vaccine development.[66] 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.[67] The COVID‑19 Clinical Research Coalition formed to coordinate and expedite results from international clinical trials on the most promising post-infection treatments.[12] 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.[8][14][15][21]

Therapeutic candidates
Evidence network of COVID-19 clinical trials of 15 therapeutic candidates.[68] Circles represent interventions or intervention groups (categories). Lines between two circles indicate comparisons in clinical trials.[68]

Phase III–IV trials

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.[3][12][69] 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.[69] As of August 2020, over 500 candidate therapeutics were in preclinical or a stage of Phase I–IV development,[1] with new Phase II–III trials announced for hundreds of therapeutic candidates during 2020.[21][1][2]

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.[3][18] By late April, hospitals in over 100 countries were involved in the trial.[70]

The individual or combined drugs undergoing initial studied are 1) lopinavir–ritonavir combined, 2) lopinavir–ritonavir combined with interferon-beta, 3) remdesivir or 4) (hydroxy)chloroquine in separate trials and hospital sites internationally.[3][18] 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,[71][72] reinstated it after the research was retracted,[73] then abandoned further use of the drug for COVID‑19 treatment when analysis showed in June that it provided no benefit.[74]

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.[3] The Solidarity project is designed to give rapid insights to key clinical questions:[3][75]

  • Do any of the drugs reduce mortality?
  • Do any of the drugs reduce the time a patient is hospitalized?
  • Do the treatments affect the need for people with COVID‑19-induced pneumonia to be ventilated or maintained in intensive care?
  • Could such drugs be used to minimize the illness of COVID‑19 infection in healthcare staff and people at high risk of developing severe illness?

Enrolling people with COVID‑19 infection is simplified by using data entries, including informed consent, on a WHO website.[3] 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.[3] 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.[3] 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.[3][75] A similar web-based study to Solidarity, called "Discovery", was initiated in March across seven countries by INSERM (Paris, France).[3][51]

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."[76]

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.[77]

Recovery Trial
Main article: RECOVERY Trial

During April, the British RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was launched initially in 132 hospitals across the UK,[78] 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.[79] 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).[80] In June, the trial arm using hydroxychloroquine was discontinued when analyses showed it provided no benefit.[81]

On 16 June the trial group released a statement that dexamethasone had been shown to reduce mortality in patients receiving respiratory support.[82] 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).[83]

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.[84] 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)."[84]

Tabulating late-stage treatment candidates

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,[21][1] 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.[22][53] 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%.[57]

COVID‑19: candidate drug treatments in Phase III–IV trials
Drug candidate Description Existing disease approval Trial sponsor(s) Location(s) Expected results Notes,
references
Remdesivir antiviral; adenosine nucleotide analog inhibiting RNA synthesis in coronaviruses investigational[85] Gilead, WHO, INSERM, NIAID China, Japan initially; extended internationally in Global Solidarity and Discovery Trials, and US NIAID ACTT Trial Mid-2020 (Chinese, Japanese trials) [21][51][86] selectively provided by Gilead for COVID‑19 emergency access;[87][88] both promising and negative effects reported in April[84][89][90]
Hydroxychloroquine or chloroquine antiparasitic and antirheumatic; generic made by many manufacturers malaria, rheumatoid arthritis, lupus (International)[91][92] CEPI, WHO, INSERM Multiple sites in China; global Solidarity and Discovery Trials June 2020 (discontinued by WHO) multiple side effects; possible adverse prescription drug interactions;[91][92] discontinued in June from WHO Solidarity trial and UK Recovery trial as "having no clinical benefit in hospitalised patients with COVID‑19";[74][81] trials[21][51]
Favipiravir antiviral against influenza influenza (China)[93] Fujifilm China April 2020 [21][9][94]
Lopinavir/ritonavir without or with interferon beta-1a antiviral, immune suppression investigational combination; lopinavir/ritonavir approved[95] CEPI, WHO, UK Government, Univ. of Oxford, INSERM Global Solidarity and Discovery Trials, multiple countries mid-2020 [21][51]
Sarilumab human monoclonal antibody against interleukin-6 receptor rheumatoid arthritis (US, Europe)[96] Regeneron-Sanofi Multiple countries Spring 2020 [21][97]
ASC-09 + ritonavir antiviral combination not approved; ritonavir approved for HIV[95] Ascletis Pharma Multiple sites in China Spring 2020 [21][98]
Tocilizumab human monoclonal antibody against interleukin-6 receptor immunosuppression, rheumatoid arthritis (US, Europe)[99] Genentech-Hoffmann-La Roche Multiple countries mid-2020 [21][1][100] Roche announced in late July that its Phase III trial of tocilizumab for treating pneumonia in hospitalized people with COVID-19 infection was ineffective[101]
Lenzilumab humanized monoclonal antibody for relieving pneumonia new drug candidate Humanigen, Inc. Multiple sites in the United States September 2020 [21][102]
Dapagliflozin sodium-glucose cotransporter 2 inhibitor hypoglycemia agent[103] Saint Luke's Mid America Heart Institute, AstraZeneca Multiple countries December 2020 [21][104]
CD24Fc antiviral immunomodulator against inflammatory response new drug candidate OncoImmune, Inc. Multiple sites in the United States 2021 [21][105]

Chloroquine and hydroxychloroquine
Main article: Hydroxychloroquine § COVID-19

Chloroquine is an anti-malarial medication that is also used against some auto-immune diseases. Hydroxychloroquine is more commonly available than chloroquine in the United States.[88] Although several countries initially used chloroquine or hydroxychloroquine for treatment of persons hospitalized with COVID‑19 (as of March 2020), the drug has not been formally approved through clinical trials,[88][106] and its use was withdrawn as a possible treatment for COVID‑19 infection when it proved to have no benefit for hospitalized patients with severe COVID-19 illness in the international Solidarity trial and UK RECOVERY Trial.[74][81]

In the United States, the experimental treatment was first authorized only for emergency use for people hospitalized but unable to receive treatment in a clinical trial,[107] but this authorization was revoked by the FDA in June, stating that it was "no longer reasonable to believe" that the drug was effective against COVID‑19 or that its benefits outweighed "known and potential risks".[108] Hydroxychloroquine is used as a prophylactic in India.[109][110]

In November 2020, a US National Institutes of Health (NIH) clinical trial evaluating the safety and effectiveness of hydroxychloroquine for the treatment of adults with coronavirus disease 2019 (COVID-19) has formally concluded that the drug provides no clinical benefit to hospitalized patients.[111][112]

Background

Chloroquine was initially recommended by Indian, Chinese, South Korean and Italian health authorities for the treatment of COVID‑19,[113] although these agencies and the US CDC noted contraindications for people with heart disease or diabetes.[88][114] In February 2020, both drugs were shown to effectively reduce COVID‑19 illness, but a further study concluded that hydroxychloroquine was more potent than chloroquine and had a more tolerable safety profile.[115][116] On 18 March, the WHO announced that chloroquine and the related hydroxychloroquine would be among the four drugs studied as part of the Solidarity clinical trial.[117]

Hydroxychloroquine and chloroquine have numerous, potentially serious, side effects, such as retinopathy, hypoglycemia, or life-threatening arrhythmia and cardiomyopathy.[91] Both drugs have extensive interactions with prescription drugs, affecting the therapeutic dose and disease mitigation.[91][92] Some people have allergic reactions to these drugs.[91][92] The NIH recommended against the use of a combination of hydroxychloroquine and azithromycin because of the resulting increased risk of sudden cardiac death.[118]

Favipiravir

Chinese clinical trials in Wuhan and Shenzhen claimed to show that favipiravir was "clearly effective".[119] Of 35 patients in Shenzhen tested negative in a median of 4 days, while the length of illness was 11 days in the 45 patients who did not receive it.[120] In a study conducted in Wuhan on 240 patients with pneumonia half were given favipiravir and half received umifenovir. The researchers found that patients recovered from coughs and fevers faster when treated with favipiravir, but that there was no change in how many patients in each group progressed to more advanced stages of illness that required treatment with a ventilator.[121]

On 22 March 2020, Italy approved the drug for experimental use against COVID‑19 and began conducting trials in the three regions most affected by the disease.[122] The Italian Pharmaceutical Agency reminded the public that the existing evidence in support of the drug is scant and preliminary.[123]

On 30 May 2020, the Russian Health Ministry approved a generic version of favipiravir named Avifavir, which proved highly effective in the first phase of clinical trials.[124][125][126]

In June 2020, India approved the use of a generic version of favipravir called FabiFlu, developed by Glenmark Pharmaceuticals, in the treatment of mild to moderate cases of COVID‑19.[127]

Remdesivir

A nucleotide analog, remdesivir is an antiviral drug candidate originally developed to treat Ebola virus disease.[128] It is specifically an adenosine analog which inserts into viral RNA chains, causing premature breaking of the chains.[129] It was studied as a possible post-infection treatment for COVID-19.[3] In May 2020, there were nine Phase III trials on remdesivir across several countries.[21][85] In November 2020, the World Health Organization updated its guideline on therapeutics for COVID-19 to include a conditional recommendation against the use of remdesivir, triggered by results from the WHO Solidarity trial.[130][131]

Adverse effects

The most common adverse effects in people treated with remdesivir were respiratory failure and blood biomarkers of organ impairment, including low albumin, low potassium, low count of red blood cells, low count of thrombocytes, and elevated bilirubin (jaundice).[90] Other reported adverse effects include gastrointestinal distress, elevated transaminase levels in the blood (liver enzymes), infusion site reactions, and electrocardiogram abnormalities.[132] Remdesivir may cause infusion‐related reactions, including low blood pressure, nausea, vomiting, sweating or shivering.[133]

Casirivimab/imdevimab

On 21 November 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID‑19 in people twelve years of age or 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 progressing to severe COVID‑19.[134] This includes those who are 65 years of age or older or who have certain chronic medical conditions.[134]

On 1 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of data on the REGN‑COV2 antibody combination (casirivimab/imdevimab), which is being co-developed by Regeneron Pharmaceuticals, Inc. and F. Hoffman-La Roche, Ltd (Roche) for the treatment and prevention of COVID‑19.[135]

Strategies

Repurposing approved drugs
See also: COVID-19 drug repurposing research

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.[17][136] 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.[137]

During the COVID‑19 outbreak, 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.[14][17][138] In the usual drug development process,[19] 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.[14][138] 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.[3][14][17]

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.[3][14][139] 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[3][140][141] – 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.[21][14][15][138][142]

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."[88]

Preliminary clinical research: Phase II trials

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.[143] 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.[143]

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%.[57] Depending on its duration (longer more expensive) – typically a period of several months to two years[143] – an average-length Phase II trial costs US$57 million (2013 dollars, including preclinical and Phase I costs).[62] Successful completion of a Phase II trial does not reliably forecast that a candidate drug will be successful in Phase III research.[53]

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.[76][3][19]

On 13 October 2020, a Phase II-III trial on a candidate treatment using a monoclonal antibody technology developed by AbCellera Biologics and Eli Lilly, bamlanivimab (LY-CoV555), was paused due to safety concerns.[144][145][146]

On 26 October 2020, Eli Lilly announced that the National Institutes of Health (NIH) ACTIV-3 clinical trial evaluating its monoclonal antibody, bamlanivimab (LYCoV555), found that bamlanivimab was not effective in treating people hospitalized with COVID-19.[147] Other studies, including the NIH ACTIV-2 trial and its own BLAZE-1 trial, will continue to evaluate bamlanivimab.[147]

According to a source reporting early-stage clinical trials on potential COVID‑19 post-infection therapies, there were over 230 Phase II trials underway or planned to start by October 2020.[2]

Emergency use authorization

On 7 October 2020, Eli Lilly and Company submitted a request for an Emergency Use Authorization (EUA) to the U.S. Food and Drug Administration (FDA) for LY-CoV555 monotherapy in higher-risk people who have been diagnosed with mild-to-moderate COVID-19.[148] Bamlanivimab (LY-CoV555) is a neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2.[148] It is being tested in the BLAZE-1, BLAZE-2, and ACTIV-3 trials.[148]

On 9 November 2020, the U.S. Food and Drug Administration issued an emergency use authorization for the investigational monoclonal antibody therapy bamlanivimab for the treatment of mild-to-moderate COVID-19.[149] Bamlanivimab is authorized for people with positive results of direct SARS-CoV-2 viral testing who are twelve years of age and older weighing at least 40 kilograms (88 lb), and who are at high risk for progressing to severe COVID-19 or hospitalization.[149] This includes those who are 65 years of age or older, or who have certain chronic medical conditions.[149]

Categories of potential therapeutics against COVID-19

According to one source (as of August 2020), diverse categories of preclinical or early-stage clinical research for developing COVID‑19 therapeutic candidates included:[21]

  • antibodies (81 candidates)
  • antivirals (31 candidates)
  • cell-based compounds (34 candidates)
  • RNA-based compounds (6 candidates)
  • scanning compounds to be repurposed (18 candidates)
  • various other therapy categories, such as anti-inflammatory, antimalarial, interferon, protein-based, antibiotics, and receptor-modulating compounds, among others for a total of some 511 compounds under development in August.[1]

Protease inhibitors
Genome of SARS-CoV-2: the grey wedges show where 3CLpro the main coronavirus protease cleaves the polyprotein.

In March 2020, the main protease (3CLpro) of the SARS-CoV-2 virus was identified as a target for post-infection drugs. The enzyme is essential for processing the replication-related polyprotein. To find the enzyme, scientists used the genome published by Chinese researchers in January 2020 to isolate the main protease.[150] Protease inhibitors approved for treating human immunodeficiency viruses (HIV) – lopinavir and ritonavir – have preliminary evidence of activity against the coronaviruses, SARS and MERS.[3][14] As a potential combination therapy, they are used together in two Phase III arms of the 2020 global Solidarity project on COVID‑19.[3][76] A preliminary study in China of combined lopinavir and ritonavir found no effect in people hospitalized for COVID‑19.[151] Novel protease inhibitors, which specifically target the protease 3CLpro, are being researched and developed in the laboratory such as CLpro-1, GC376, and Rupintrivir.[152][153][154]

Preclinical research

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,[8] such as experiments to determine effective doses and toxicity in animals, before a candidate compound is advanced for safety and efficacy evaluation in humans.[155] 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.[10][156][157][158] 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%.[57]

Broad-spectrum therapeutics

In 2021, the importance of drug repurposing for COVID-19 led to the establishment of broad-spectrum therapeutics.[159] Broad-spectrum therapeutics are effective against multiple types of pathogens.[160] Such drugs have been suggested as potential emergency treatments for future pandemics.[161][162]

See also

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