COVID-19 Vaccines and Drugs: Medicine’s Armory

Issue 37 / February 2021

COVID-19 Special

The first COVID-19 vaccine, as well as several antiviral drugs, have been granted emergency use approval in the West. While this is nothing short of amazing, challenges of manufacturing, distribution and acceptance need to be overcome before the world can begin to return to some semblance of normality.

ince August 2020, pharmaceutical companies and governments have moved swiftly to analyse clinical trial results and ramp up manufacturing of yet-unapproved COVID-19 vaccines and drugs. Widespread vaccination of populations will be crucial to protect people from becoming infected with SARS-CoV-2, while the drugs will help to prevent infection as well as treat people who are already infected.

China and Russia have approved vaccines that were developed in their respective countries, and started immunising their populations months ago¹. In December 2020, the US, UK and Canada granted emergency approval to the mRNA vaccine developed by Pfizer and BioNTech, and the first doses have been delivered to immunise healthcare workers and high-risk individuals such as nursing home residents. Singapore has approved the vaccine and plans to immunise its population by the third quarter of 2021².

Vaccine Candidates in clinical trials

Vaccine Candidates
will be tested
in upcoming clinical trials
in 2021

Another mRNA vaccine, developed by Moderna, was approved by the US for emergency use soon after the Pfizer-BioNTech vaccine. As of 3 January 2021, the viral vector vaccine from AstraZeneca/University of Oxford has been approved for emergency use by the UK and India, while the viral vector vaccine from Johnson & Johnson may be next. This is significant because the AstraZeneca vaccine is cheaper than the Pfizer and Moderna ones ($3-$4 vs $20 per dose for the Pfizer vaccine and $25 to $37 per dose for the Moderna vaccine; all three vaccines require two doses), and may be easier to transport and store³. The Johnson & Johnson vaccine requires only one dose. Although these are the frontrunners in the vaccines race, it will be difficult to produce sufficient doses to vaccinate all or even most of the world’s populations. The good news is that more than 20 additional vaccines are in the final stage (Phase 3) of clinical testing, with 200 more at earlier stages of development, and will help fill this gap¹. Table 1 shows some of the vaccine candidates that are currently being evaluated in clinical trials or that are scheduled for testing in upcoming trials. An earlier version of this article, published in August 2020, contains a description of the different types of vaccines being developed.

Besides vaccines, drugs to treat individuals who are already infected with COVID-19 are being developed and tested at a rapid pace. A few drugs, including Remdesivir from Gilead Sciences and the REGN-COV2 antibody cocktail from Regeneron Pharmaceuticals, are already being used for certain hospitalised COVID-19 patients. Other drugs are being developed to treat the excessive inflammation that becomes the main concern in severe cases of COVID-19^4,5. Some of the antiviral and anti-inflammatory drugs that are currently being tested or will be tested soon in clinical trials are shown in Table 1.

As we move into 2021, other concerns such as manufacturing, distribution and the public’s response to vaccines will take centre stage. Governments and companies have already anticipated these issues and have forged partnerships to rapidly produce millions of doses of vaccines and drugs, and deliver them under proper conditions to where they are needed. Many of the frontrunner vaccines’ manufacturers have been ramping up production alongside R&D and clinical trials, with the help of funding from governments and non-profit organisations such as The Coalition for Epidemic Preparedness Innovations (CEPI).

Click here to see an earlier version of this article.

Table 1.

Some of the vaccine candidates currently being developed

In clinical trials

Whole virus vaccines

Vaccine Candidate

CoronaVac

Developed By

Sinovac Biotech (China)

How It Works

Whole SARS-CoV-2 virus that has been inactivated so it does not replicate in the body.

Stage of Development and Early Results

Phase 1 and 2 clinical trials started in April 2020. More than 90% of participants showed a neutralising antibody response, and none experienced severe side effects. A Phase 3 trial started on 21 July 2020 in Brazil and 11 August 2020 in Indonesia⁶.

Vaccine Candidate

BBIBP-CorV

Developed By

Beijing Institute of Biological Products (China)

How It Works

Whole virus inactivated by treatment with β-propiolactone

Stage of Development and Early Results

Phase 1 and 2 trials showed that the vaccine induced strong neutralising antibody responses in 100% of participants aged 18 to 59, and >90% of participants aged ≥607. No severe side effects were reported. Two 4-µg doses, given three weeks apart, gave the strongest neutralising antibody response.

Subunit vaccines

Vaccine Candidate

NVX-CoV2373

Developed By

Novavax (US), The Coalition for Epidemic Preparedness Innovations (CEPI), the European Commission, and the Paul Ehrlich Institute (Germany)

How It Works

Pre-fusion S protein linked to a nanoparticle (Novavax’s proprietary technology), injected together with Novavax’s Matrix-M adjuvant⁸. Goal is to cause immune cells called antigen-presenting cells to move to injection site, stimulating neutralising antibody and T-cell responses against the virus.

Doses required: 2

Storage/transport conditions: 2°C to 8°C (refrigerated)

Stage of Development and Early Results

Vaccine Candidate

SCB-2019 (S-Trimer)

Developed By

Clover Biopharma-ceuticals (China)

How It Works

Native (probably pre-fusion) S protein of SARS-CoV-2, administered together with Dynavax’s FDA-approved CpG1018 adjuvant (used in an approved vaccine for Hepatitis B virus)¹⁰. By injecting this in the muscle, the goal is to induce neutralising antibodies against the virus.

Stage of Development and Early Results

Phase 1 trial started in late June 2020 to evaluate the safety and ability to provoke an immune response of various doses of SCB-2019.

Viral vector vaccines

Vaccine Candidate

Ad5-nCoV

Developed By

CanSino Biological (China) and Academy of Military Medical Sciences’ Institute of Biotechnology (China)

How It Works

Entire spike protein in an adenovirus type 5 (Ad5) vector that does not replicate well in the body. By injecting this in the muscle, the goal is to induce neutralising antibodies against the virus.

Dose required: 1

Storage/transport conditions: 2°C to 8°C (refrigerated)

Stage of Development and Early Results

Phase 1 trial, evaluating safety and antibody response to three different vaccine doses, is ongoing. Results showed increases in neutralising antibodies and T-cells, with peaks at 28 days and 14 days, respectively¹¹. A few participants in high-dose group reported more severe fever, fatigue and/or muscle pain. High pre-existing levels of antibodies against adenovirus (a common virus) reduced the neutralising antibody response to the vaccine.

Based on results of Phase 1, Phase 2 evaluated safety and immunogenicity of low and medium doses of vaccine vs placebo in 500 subjects. Preliminary results showed strong neutralising antibody responses against live SARS-CoV-2 in 47% to 51% of participants, and virus-specific T-cell responses in 88% to 91% of participants¹¹. The low dose (5×1010 viral particles) was as effective as the medium dose. Phase 3 clinical trials, testing Ad5-CoV against placebo, started in August and September 2020 in Pakistan, Russia and Saudi Arabia. Approved by the Central Military Commission of the People’s Liberation Army in June 2020.

Vaccine Candidate

AZD1222 (previously known as ChAdOx1 nCoV-19)

Developed By

Jenner Institute, University of Oxford (UK) and AstraZeneca (UK). AstraZeneca to manufacture and distribute vaccine.

How It Works

S protein in a chimpanzee adenoviral vector that does not replicate in the body. Goal is to inject into the muscle and stimulate production of neutralising antibodies and T-cells against the virus.

Doses required: 2

Storage/transport conditions: 2°C to 8°C (refrigerated)

Stage of Development and Early Results

Phase 1 and 2 trials testing safety and immunogenicity in 510 subjects started end April 2020, expected to complete in May 2021. Preliminary results showed that two doses of the vaccine provoked virus-specific T-cells and neutralising antibodies, without causing serious side effects¹³.

Phase 2 and 3 trials are being conducted in the UK, and a Phase 3 trial is ongoing in Brazil. Preliminary results from 11,636 participants showed 90% efficacy in participants given a half dose of vaccine followed by a full dose ≥1 month later, and 62% efficacy in participants given two full doses ≥1 month apart¹⁴. No serious side effects have been observed thus far.

The same team previously used this technology for MERS and obtained strong immune responses in clinical trials.

The UK government has committed ₤65.5 million towards clinical trials. The US government’s National Institute of Allergy and Infectious Diseases (NIAID) and Biomedical Advanced Research and Development Authority (BARDA) are also funding the Phase 3 trial.

Vaccine Candidate

Ad26.COV2-S (also known as JNJ-78436735)

Developed By

Johnson & Johnson (US) and BARDA (US government)

How It Works

Ad26.CoV2-S consists of proteins from SARS-CoV-2 incorporated in a viral vector that does not replicate.

Dose required: 1

Storage/transport conditions: 2°C to 8°C (refrigerated)

Stage of Development and Early Results

Phase 1 and 2 clinical trials, which started in late July 2020, has so far shown that the vaccine induced strong neutralising antibody responses and no serious side effects. A Phase 3 trial (ENSEMBLE) of up to 60,000 participants started in August 2020¹⁵. Johnson & Johnson aims to apply for Emergency Use Authorisation (EUA)—the U.S. Food and Drug Administration (FDA)’s rush approval for urgent use—in early 2021, which would make first batches of the vaccine available for high-risk people¹⁶.

Johnson & Johnson has used this virus vector platform in its approved Ebola vaccine, as well as its HIV, RSV and Zika vaccine candidates¹⁷.

Johnson & Johnson and BARDA have committed a total of US$1 billion to this effort.

Vaccine Candidate

mRNA 1273

Developed By

Moderna (US) and NIAID (US government)

How It Works

mRNA encoding the entire pre-fusion S protein of SARS-CoV-2, wrapped in a lipid nanoparticle. Goal is to inject into the muscle and stimulate a neutralising antibody response against the virus¹⁸.

Based on work with the respiratory syncytial virus which found that only the pre-fusion form of the S protein (before virus melds with the host cell membrane) provokes a strong neutralising antibody response.

Doses required: 2 (1 month apart)

Storage/transport conditions: Stable at 2°C to 8°C (refrigerated) for 30 days (according to Moderna); long-term storage at -70°C (frozen in dry ice)

Stage of Development and Early Results

Phase 1 trial with 45 subjects, evaluating safety, side effects and ability to provoke an immune response to three different vaccine doses, started in March 2020. On May 18, Moderna reported promising results in eight Phase 1 participants, showing that the vaccine induced strong immune responses and was well tolerated at low and medium doses. The high dose produced severe side effects in three participants¹⁸.

Phase 2 included only the low and medium doses. Phase 3 enrolled 30,000 participants, with almost all having received both vaccine doses. Interim results showed almost 95% efficacy for preventing COVID-19 infections vs placebo (five symptomatic COVID-19 cases in vaccine arm versus 95 cases in placebo arm)¹⁹. Appears to prevent severe disease (severe cases [11] occurred only in the placebo arm). More details about immune responses in participants should be released soon.

The US government has committed ~US$955 million towards clinical trials and manufacturing¹⁹.

Moderna received an EUA from the FDA on 18 December 2020. It has also applied to the European Medicines Agency (EMA) and started a rolling review application with the Health Sciences Authority in Singapore for emergency use²⁰.

Vaccine Candidate

BNT162b2 mRNA

Developed By

BioNTech (Germany) and Pfizer (US)

How It Works

mRNA coding for the S protein of SARS-CoV-2

Doses required: 2 (3 weeks apart)

Storage/transport conditions: -70°C (frozen in dry ice)

Stage of Development and Early Results

Phase 1 and 2 trials of mRNA vaccine BNT162 in several hundred healthy people are ongoing²¹. Preliminary results showed that BNT162 could induce neutralising antibody and T-cell responses similar to those in people recovering from COVID-19.

Phase 2 and 3 trials of more than 43,000 people (some at higher risk of COVID-19) started in end July 2020. Pfizer reported interim results, showing a 95% vaccine efficacy²².

Pfizer is developing its own -70°C cold-chain distribution to vaccination sites, where many people could be vaccinated in one day.

The UK approved the vaccine for immediate use in high-risk individuals on 2 December 2020. First vaccine to be granted EUA status by the FDA on 11 December 2020. Healthcare workers and high-risk individuals have already started to receive the vaccine.

Vaccine Candidate

ARCT-021 (previously known as LUNAR-COV19)

Developed By

Arcturus Therapeutics (US), Duke-NUS Medical School (Singapore), Catalent (US) and the Singapore Government. Catalent will perform large-scale manufacturing (up to 100s of millions of doses)

How It Works

Self-replicating mRNA vaccine coding for the S protein of SARS-CoV-2.

Stage of Development and Early Results

Duke-NUS researchers performed preclinical testing, showing that the vaccine induced strong neutralising antibody and T-cell responses. Ongoing Phase 1 and 2 clinical trials are evaluating the efficacy of a one-dose and two-dose regimen of ARCT-021²³.

The Singapore government has provided S$220 million funding towards the vaccine’s development and manufacturing, and will own the rights within Singapore²⁴.

Vaccine Candidate

CVnCoV(mRNA vaccine)

Developed By

CureVac (Germany) and CEPI

How It Works

mRNA coding for a part of the S protein of SARS-CoV-2²⁴.

Stage of Development and Early Results

Phase 1 started end June 2020, and will evaluate safety, side effects and ability to provoke an immune response of several vaccine doses in 168 healthy subjects. Phase 2, with a target of 660 subjects (some aged >60 years) started in August 2020.

CureVac has extensive experience working with mRNA therapies and is planning to build a new production facility in the next two years. Together with its present facilities, this would enable it to manufacture several billion vaccine doses per year²⁵.

The European Commission has offered up to €80 million towards development and manufacturing.

DNA vaccines

Vaccine Candidate

INO-4800

Developed By

Inovio Pharmaceuticals and CEPI

How It Works

DNA vaccine that matches the DNA sequence of the virus. Injected through the skin, followed by electroporation²⁶. Goal is for the DNA to go into the cells, and cause virus-specific antibodies and T-cells to be produced.

Doses required: 2

Storage/transport conditions: room temperature

Stage of Development and Early Results

Early results of Phase 1 trial showed antibody and T-cell responses in 94% of subjects and no serious side effects eight weeks after receiving the vaccine²⁶.

A Phase 2 and 3 trials to evaluate the efficacy of INO-4800 against placebo is expected to start soon²⁷.

Repurposed vaccines

Vaccine Candidate

Repurposed Bacillus Calmette-Guerin (BCG) vaccine, currently used for TB in some countries

How It Works

The BCG vaccine may stimulate the innate immune system, the body’s first line of defense against invaders, which could help to prevent the SARS-CoV-2 virus from infecting cells and reproducing. Still need more evidence that it works against SARS-CoV-2.

Stage of Development and Early Results

Large trials in the US, Australia and the Netherlands are ongoing to evaluate the efficacy of BCG vaccine for respiratory illnesses including COVID-19.

One study, which looked at data until 22 April 2020, reported that countries with high rates of BCG vaccination tended to have lower COVID-19 mortality²⁸. However, another study which looked at data until August 2020 did not find a relationship between BCG vaccination rates and COVID-19 deaths²⁹.

Will be tested in upcoming clinical trials in 2021

Vaccine Candidate

DNA vaccine

Developed By

Sanofi Pasteur (France) and GlaxoSmithKline (GSK) (UK)

How It Works

DNA vaccine that codes for a protein (antigen) that will stimulate an immune response against SARS-CoV-2, administered together with GSK’s adjuvant.

Stage of Development and Early Results

Clinical trials expected to start in Q3 or Q4 2020 and available by Q3 or Q4 2021.

Vaccine Candidate

Clec9A-RBD (“Fusion” vaccine)

Developed By

NUS Medicine (Singapore) and Monash University (Australia)

How It Works

Consists of an antibody (stimulates the immune response more generally) fused to a protein called an antigen that stimulates a specific immune response against SARS-CoV-2³⁰. The vaccine may help to boost the weakened immune systems of elderly individuals against the virus.

Dose required: 1

Stage of Development and Early Results

Currently being tested in preclinical studies. Clinical trials expected to start end 2021.

Antiviral and anti-inflammatory drugs

While vaccines are typically used to protect healthy people from getting sick with COVID-19, antiviral drugs can be used to prevent disease in healthy people or to treat people who already have the disease. Some antiviral drugs prevent the virus from infecting cells, which is the first step in establishing an infection. Other antivirals work by binding to virus particles already present in a person, targeting the virus for destruction by the immune system. Besides antivirals, other drugs that suppress the inflammatory response are being tested in more severe COVID-19 infections, in which inflammation is a major problem. Most of the antivirals that are currently being tested or that are scheduled for testing in 2020 are antibodies or small molecules, a class of chemical compounds (Table 2).

One small molecule, Remdesivir, was originally developed to treat Ebola virus infection. An early report indicated that Remdesivir sped up recovery in hospitalised COVID-19 patients, prompting the FDA to grant an emergency use authorisation (EUA) to make it available for certain high-risk COVID-19 patients. However, a large trial conducted by the World Health Organization of Remdesivir, Hydoxycholoroquine, Lopinavir/Ritonavir and Interferon found that none of these therapies reduced mortality or the need for ventilation, nor did they shorten hospital stays, compared with standard care. Nonetheless, combinations of Remdesivir with other therapies remain promising options for treating COVID-19 patients.

Antiviral Candidates in clinical trials

Antiviral Candidates
will be tested
in upcoming clinical trials
in 2021

Antibodies isolated from the blood of patients who have recovered from COVID-19 can be potent antiviral agents, useful for protecting people against infection and treating the disease in COVID-19 patients. The dual-antibody cocktail REGN-COV2, developed by Regeneron Pharmaceuticals, binds to two different sites on the viral S protein, essentially giving the drug two shots on goal.

REGN-COV2 has shown strong results in reducing viral levels and reducing the need for further medical visits in COVID-19 outpatients, especially those who had not raised antibodies against the virus when treatment began. Another antibody, AOD01, was identified from screening B-cells (the cells that produce antibodies) as part of a Singapore whole-of-government effort, involving scientists at the DSO National Laboratories and NUS Medicine, as well as collaborators at the Ministry of Defence, Ministry of Health and the Economic Development Board. AOD01 had one of the highest neutralising activities against SARS-CoV-2 reported to date in cell culture (the ability to block the virus from infecting cells). A clinical trial of AOD01 is expected to start soon.

Another candidate, APN01, is neither an antibody or a small molecule. Instead, it is a protein that mimics the receptor used by SARS-CoV-2 to enter cells in the body. The hope is that APN01 will bind to the virus, thus preventing the virus from binding to its receptor and infecting cells. Results from clinical trials are expected next year.

Some of these drugs are repurposed existing drugs, which have already been tested in clinical trials and approved by regulatory authorities for another disease.

Table 2.

Some of the antiviral drug candidates currently being developed

In clinical trials

Mimic of virus receptor

Vaccine Candidate

APN01

Developed By

Apeiron Biologics (Austria)

How It Works

Mimic of the human angiotensin converting enzyme 2 (rhACE2), the protein receptor that the virus uses to get into cells³¹. Goal is for rhACE2 to bind the virus, preventing it from binding to the ACE2 receptor on cells. APN01 also reduces harmful inflammation in lungs and prevents acute respiratory distress syndrome.

Stage of Development and Early Results

Phase 2 testing of APN01 vs placebo in 200 patients is ongoing. Skipped Phase 1 and went directly into Phase 2 testing after regulatory approval in April³¹.

Vaccine Candidate

Actemra® / Roactemra® (tocilizumab) (Original indication: rheumatoid arthritis; cytokine storm side effect of CAR-T therapy)

Developed By

Roche (Switzerland) and BARDA (US government)

How It Works

Inhibits function of Interleukin-6 (IL-6), an important protein in the inflammatory response. Goal is to reduce excess inflammation in severe COVID-19³².

Stage of Development and Early Results

A clinical trial in France showed a reduction in deaths or life support interventions, vs a control group³².

Safety and efficacy of the drug plus standard of care being tested in a Phase 3 trial (COVACTA), vs placebo plus standard of care, in patients hospitalised with severe COVID-19. Actemra reduced the risk of death by 29%³³. However, another trial showed no difference in clinical worsening with Actemra vs standard of care³⁴.

Another Phase 3 trial (REMDACTA) testing the efficacy and safety of the drug plus Remdesivir (see below) vs placebo plus Remdesivir in patients hospitalised with severe COVID-19 started on 28 May 2020³⁵.

Vaccine Candidate

REGN-COV2

Developed By

Regeneron Pharmaceuticals (US)

How It Works

Cocktail of two antibodies (casirivimab and imdevimab) that bind to the S protein of SARS-CoV-2.

Stage of Development and Early Results

Results from a Phase 1 trial showed that REGN-COV2 is likely safe. Phase 2 and 3 trials showed that REGN-COV2 reduced by 10-fold the amount of virus and 57% the need for further medical visits in COVID-19 outpatients³⁶. Patients who did not have antibodies against the virus (had not raised an immune response) at the start of the trial responded better than those with antibodies.

Based on these strong results, the FDA issued an EUA for REGN-COV2 on 21 November 2020, for COVID-19 patients at high risk for progression to severe disease³⁷.

Vaccine Candidate

Bamlanivimab (LY3819253 or LY-CoV555), human monoclonal antibody specific for SARS-CoV-2

Developed By

AbCellera Biologics (Canada), Eli Lilly (US), and the Vaccine Research Center, NIAID (US)

How It Works

Starting with 500 antibodies obtained from the blood of one patient who had recovered from COVID-19, AbCellera used its platform to select a few top antibody candidates and is now testing one (LY3819253).

Stage of Development and Early Results

Phase 1 trial of patients hospitalised with severe COVID-19³⁸ and Phase 2 trial of patients with mild or moderate COVID-19³⁹ are ongoing. Interim results from the Phase 2 trial suggested that Bamlanivimab could reduce number of hospitalisations, however, findings were not definitive.

In May 2020, AbCellera received CAD$175.6 million in support from the Government of Canada towards developing antibody therapies against COVID-19. In November 2020, the FDA granted the drug an EUA for mild-to-moderate COVID-19 patients at high risk for progressing to severe disease⁴⁰.

Antibodies

Vaccine Candidate

VIR-7831 and VIR-7832, human monoclonal antibodies targeting ACE2 receptor of SARS-CoV-2

Developed By

Vir Biotechnology (US), NIAID (US), GSK (UK), WuXi Biologics (China), Biogen (US)

How It Works

Derived from an antibody obtained from the blood of a patient who had recovered from SARS. The antibody targets ACE2, the receptor used by the virus to enter cells, and could neutralise SARS-CoV-2 in cell culture⁴¹.

Stage of Development and Early Results

Phase 2 and 3 trials (without a Phase 1 trial) of VIR-7831 started in August 2020, and Phase 1b and 2a trials of VIR-7832 are expected soon. Results from the VIR-7831 trial could be announced in January 2021⁴².

Vaccine Candidate

IFX-1

Developed By

InflaRx (Germany)

How It Works

Antibody specific for C5a, a component of the complement system that is involved in inflammation. This may be useful in treating more severe COVID-19 disease⁴¹.

Stage of Development and Early Results

Results from a small exploratory Phase 2 study of 30 patients showed that IFX-1-treated patients had a 35% to 50% lower death rate than patients who did not get IFX-1, but the study was too small to make definitive conclusions⁴³.

Larger Phase 2 and 3 trials of 390 COVID-19 patients with severe pneumonia are ongoing, and are expected to complete in August 2021⁴⁴.

Vaccine Candidate

Remdesivir

Developed By

Gilead Sciences (US) and NIAID (US government)

How It Works

RNA polymerase inhibitor (blocks RNA polymerase enzyme that virus needs to replicate). Shown to inhibit SARS-CoV-2 in cell culture; case studies have also reported some improvement in patients with severe COVID-19⁴⁵.

Stage of Development and Early Results

Gilead is conducting two Phase 3 “SIMPLE” trials (one for severe and one for moderate COVID-19), of five-day and 10-day Remdesivir treatment regimens plus standard of care, vs standard of care alone. The NIAID is conducting a Phase 2 trial of 1,059 hospitalised COVID-19 patients with lower respiratory infection. Independently, the WHO is conducting a large international trial (“Solidarity”) of 12,000 hospitalised COVID-19 patients to evaluate Remdesivir and other drugs. Conflicting results have emerged from the SIMPLE and NIAID trials vs the Solidarity trial.

Early results from the first SIMPLE trial in severe COVID-19 patients showed similar time to clinical improvement for patients on the five-day and 10-day treatments (>50% recovered by Day 14). Most patients did not have severe side effects⁴⁶.

Results from the second SIMPLE trial in patients with moderate COVID-19 showed that five-day treatment plus standard of care led to 65% higher rate of clinical improvement at Day 11 vs standard of care alone⁴⁷.

The NIAID trial showed that patients on Remdesivir recovered more quickly than those on placebo (10 vs 15 days), and had 27% lower mortality at month 1⁴⁸. On 1 May 2020, Remdesivir received EUA from the FDA for use in select hospitalised COVID-19 patients.

However, preliminary results (released in October 2020) from the WHO’s Solidarity trial indicated that Remdesivir had no effect on mortality, need for ventilation and length of hospital stay⁴⁹.

Singapore’s Involvement

Singapore’s National Centre for Infectious Disease (NCID) is one of the centres for the two SIMPLE Gilead clinical trials and the NIAID trial, with 90 Singaporean patients with severe COVID-19 enrolled.

The Director of the Infectious Disease Research and Training Office of the National Centre for Infectious Diseases at Tan Tock Seng Hospital, Singapore, Dr David Lye, is the second author on the New England Journal of Medicine paper about the results of the first SIMPLE trial.

Mimic of virus receptor

Vaccine Candidate

Lopinavir and Ritonavir (Kaletra®) (original indication: HIV infection)

Developed By

Abbvie (US)

How It Works

Combination of two protease inhibitors that block the HIV protease, an enzyme that HIV needs to infect cells. Rationale is that the drug combination could also block the protease of SARS-CoV-2.

Stage of Development and Early Results

Currently tested in more than 20 trials (according to Clinicaltrials.gov) to treat COVID-19 or to prevent disease in people who have come into close contact with a confirmed case.

Clinical trial in patients with severe COVID-19 at a hospital in Wuhan, China showed no benefit of combination over standard of care⁵⁰.

Singapore’s Involvement

A study led by Prof Dean Ho at NUS, using an AI platform (IDentif.AI), identified the combination of Remdesivir with Lopinavir and Ritonavir as an optimal therapy, 6.5 times more potent than Remdesivir alone. Published in a preprint paper (not peer-reviewed)⁵¹.

Identif.AI also predicted that Iopinavir and Ritonavir, as well as Hydroxychloroquine and Azithromycin would not be effective. The WHO Solidarity trial showed no effect with Iopinavir and Ritonavir or Hydroxychloroquine in COVID-19, but did not evaluate combinations of these therapies with other therapies⁴⁹.

Vaccine Candidate

Dexamethasone (original indications: allergies, skin conditions, gastrointestinal disorders, rheumatic disorders, endocrine disorders, etc.)

Developed By

Multiple companies manufacture this generic drug

How It Works

Dexamethasone is a steroid that reduces inflammation. Goal is to combat lung inflammation in severe COVID-19 disease, to prevent progression to respiratory failure and death.

Stage of Development and Early Results

The RECOVERY trial of hospitalised COVID-19 patients compared 4,321 patients on standard care vs 2,104 patients on standard care plus Dexamethasone. Results from this trial showed that Dexamethasone reduced deaths most effectively (by 35%) in the most severe patients, who required mechanical ventilation⁵².It was less effective in less severe patients, who required oxygen support only (reduced deaths by 20%), and not effective in the least severe patients who did not require respiratory support.

Vaccine Candidate

Camostat mesylate (original indication: chronic pancreatitis)

Developed By

Clinical trial performed by Yale University

How It Works

Inhibits the TMPRSS2 protease, which is required for the SARS-CoV-2 virus to infect cells.

Stage of Development and Early Results

Phase 2a trial of 114 people with early-stage COVID-19 (within two days of diagnosis). Efficacy for reducing viral load (number of virus particles) and lessening COVID-19 symptoms will be evaluated at two, seven and 14 days after starting seven-day treatment regimen⁵³.

A small study evaluating the efficacy of camostat mesylate in 11 patients with severe COVID-19 showed that it improved disease severity and reduced inflammation⁵⁴.

Vaccine Candidate

Favipiravir (Avigan®) (original indication: influenza)

Developed By

Tayoma Chemical, a subsidiary of Fujifilm

How It Works

Inhibits RNA polymerase of virus, thus preventing viral replication.

Stage of Development and Early Results

Interim clinical trial results reported on 20 May 2020 did not show efficacy against COVID-19⁵⁵. Stanford Medicine is testing the drug in 120 newly diagnosed COVID-19 outpatients to see if it reduces virus shedding.

Will be tested in upcoming clinical trials in 2021

Vaccine Candidate

COVI-SHIELD antibody cocktail/COVI-GUARD antibody

Developed By

Sanofi Pasteur (France) and Sorrento Therapeutics, Mount Sinai Health System, University of Texas Medical Branch (all US-based)

How It Works

Cocktail of three antibodies will include Sorrento’s star SARS-CoV-2 neutralising antibody, STI-1499, reportedly able to stop 100% of infections by the virus⁵⁶.

Stage of Development and Early Results

Phase 1 trial of COVI-GUARD (STI-1499 alone) started in July 2020⁵⁴. Trials of COVI-SHIELD are expected to start soon.

Vaccine Candidate

AOD01, human monoclonal antibody that neutralises SARS-CoV-2

Developed By

DSO National Laboratories and NUS Yong Loo Lin School of Medicine (Singapore)

How It Works

One of five human monoclonal antibodies isolated from the blood of patients who recovered from COVID-19, using a high-throughput screening method that the team developed. The ability of the antibodies to block SARS-CoV-2 from infecting cells is the highest reported to date⁵⁸.

Dose required: 1

Stage of Development and Early Results

Clinical trials of AOD01 projected to start in the upcoming months⁵⁸.

Singapore’s Involvement

Only COVID-19 therapy to be wholly developed in Singapore.

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Issue 37 / February 2021

COVID-19 Special