With much of the world living in lockdown, the spread of the new coronavirus, Sars-CoV-2, that was first detected in China late last year is beginning to slow in some places.
As of April 19, 2.4 million had been infected and 165,000 killed by Covid-19, the disease caused by the virus.
While a safe, effective vaccine is still more than a year away, researchers are rushing to repurpose existing drugs and non-drug therapies, and testing promising experimental drugs that were already in clinical trials.
Even moderately effective therapies or combinations could dramatically reduce the crushing demand on hospitals and intensive care units, changing the nature of the risk the new pathogen represents to populations and healthcare systems.
New drugs, together with new diagnostics, antibody tests, patient- and contact-tracing technologies, disease surveillance and other early-warning tools, mean the anticipated next ‘wave’ of the global pandemic does not have to be nearly as bad as the first.
More than 70 vaccine candidates are also in development around the world, with at least five in preliminary testing in people. Here are some of them:
Gilead Sciences: Remdesivir
Type: Drug
Status: Repurposed experimental
Early results: 0-3 months.
Antiviral drug, originally developed to combat RNA viruses including respiratory syncytial virus. At least 13 trials underway in China, Europe and the United States with preliminary results from two Chinese trials expected as soon as April 2020. A February assessment by the WHO flagged this candidate as the most promising for battling Covid-19.
Caveats
Initial data are expected to come from studies of patients with relatively severe Covid-19. Because antivirals work best when patients are healthier, those results may show limited effectiveness.
Hydroxychloroquine/chloroquine
Type: Drug
Status: Repurposed
Early results: 0-3 months
Malaria drug also believed to have antiviral activity. Blocked Sars-CoV-2 entry into cells in an in-vitro experiment. In one small French study, some Covid-19 patients showed improvements but there was no way to know if the drug was the reason. Results published in April from another study in France and one in China found no benefit in patients treated with the drug. Dozens more clinical studies are underway around the world.
Roche: Actemra (tocilizumab)
Type: Drug
Status: Repurposed
Early results: 0-3 months
Monoclonal antibody approved for rheumatoid arthritis and also for treating the ‘cytokine storm’ immune overresponse in cancer patients. Fifteen registered trials in China, Europe and the United States are testing it on Covid-19 patients, alone or in comparison to other therapies. One French trial is looking at 28-day effects on Covid-19 in patients with advanced or metastatic cancer.
Sanofi, Regeneron Pharmaceuticals: Kevzara (sarilumab)
Type: Drug
Status: Repurposed
Early results: 0-3 months.
Monoclonal antibody approved for inflammatory arthritis, and in trials targeting the ‘cytokine storm’ immune response in severely ill Covid-19 patients. Regeneron’s chief scientific officer has said initial data on effectiveness could come by late April.
Norvatis, Incyte: Jakavi (ruxolitinib)
Type: Drug
Status: Repurposed
Early results: 0-3 months.
Developed to treat inflammatory and autoimmune diseases, and in late-stage development as a cream for atopic dermatitis. One trial each in Canada and Mexico will test the drug in Covid-19 patients with severe respiratory symptoms associated with the ‘cytokine storm’ immune response, with preliminary results expected by June 2020. In the US, Novartis established a managed access programme for use in severe/very severe Covid-19 illness on April 7.
Moderna/Niaid: mRNA 1273
Type: Vaccine
Status: Experimental
Early results: 0-3 months
RNA vaccine made with messenger-RNA (mRNA) encoding the spike protein of SARS-CoV-2 encapsulated in a lipid nanoparticle. The phase 1 trial with 45 subjects aged 18-55 at three locations in the United States will evaluate the vaccine’s safety and provide early data on the immune response it induces. Trial completion is anticipated to be June 1, 2020.
Convalescent plasma
Type: Non-drug therapy
Early results: 0-3 months.
Blood plasma from recovered Covid-19 patients is transfused into patients who are currently ill, in the hope the freshly-made antibodies it contains will help fight the virus. The method has been used for more than 100 years and carries little risk of harm or side effects. Small case studies suggest it may help reduce virus levels, and controlled trials are in progress in China, Europe and the United States to gather stronger evidence for a benefit. Results published in April from a study in 10 patients with severe illness in China found significant improvement compared to similar patients who did not receive the treatment.
Caveats
Immediately available and already in limited use, but supply of plasma from recovered patients may not be sufficient to meet all needs. Further studies of recovered patients must also determine if everyone produces a full immune response to the infection, including ‘neutralising antibodies’ at sufficiently high levels to become donors.
Abbvie: Kaletra (lopinavir/ritonavir)
Type: Drug
Status: Repurposed
Early results: 0-3 months.
Antiviral combination used to treat and prevent HIV infections. More than twenty trials around the world are testing the drug as a Covid-19 treatment or post-exposure prophylaxis for people with high-risk close contact with a confirmed case. Initial results expected as soon as May 2020.
Caveats
One randomised controlled trial in China published results in March showing no differences in viral load or 28-day mortality among 199 patients. Median time to clinical improvement was one day shorter in patients taking the drug. However, the same investigators, doctors at Jinyintan Hospital in Wuhan, said in April that they believe Kaletra, as well as a second drug, bismuth potassium citrate, helped some Covid-19 patients.
Chongqing public health medical centre, Chongqing Sidemu Biotechnology Co Ltd: NKG2D-ACE2 CAR-NK cells
Type: Non-drug therapy
Status: Experimental
Early results: 0-3 months.
NKG2D receptor for the immune system’s natural killer (NK) cells paired with the ACE-2 receptor that the coronavirus uses to enter human cells. A multicentre Phase 1/2 trial in 90 patients is testing whether this cell therapy can prevent the Sars-CoV-2 virus from entering cells and multiplying, and will look at efficacy over 28 days in patients with severe or critical Covid-19 pneumonia.
Novavax: NVX-CoV2373
Type: Vaccine
Status: Experimental
Early results: 0-3 months.
Novavax said its Matrix-M adjuvant would be used with the vaccine candidate – NVX-CoV2373 – to enhance immune responses. Trials in 130 adults is expected to begin in mid-May with preliminary immunogenicity and safety results in July, according to the firm.
Caveats
Strong immunogenicity in animal tests, but might require two doses in humans, which would limit supply.
Apeiron Biologics: RhACE2 APN01
Type: Drug
Status: Experimental
Early results: 3-6 months
A recombinant human angiotensin converting enzyme 2 (rhACE2) under Phase-2 clinical development in ALI (Acute Lung Injury) and PAH (Pulmonal arterial hypertension). This synthetic version of the human protein that the novel coronavirus uses to enter cells is being tested in Austria to see if it can block viral entry and decrease viral replication in Covid-19 patients, reducing deaths or need for mechanical ventilation. Preliminary results from the trial that was announced on April 2 are expected in September 2020.
Shenzhen Geno-Immune Medical Institute: Lentiviral Minigene Vaccines
Type: Vaccine
Status: Experimental
Early results: 3-6 months
Engineered minigenes encoding viral antigens; lentiviral vector designed to infect dendritic and T cells to induce immunity. The trial in 100 adults in Shenzen, China, is expected to be complete by July 31, 2020.
Murdoch children’s Research Institute; UMC UTRECHT: BCG TB vaccine
Type: Vaccine
Status: Repurposed
Early results: 3-6 months
Bacillus Calmette-Guérin tuberculosis vaccine that induces a broad innate immune-system response, which has been shown to protect against infection or severe illness with other respiratory pathogens. Large trials in Australia and the Netherlands are testing whether using BCG to rev-up immune defences in health workers and the elderly reduces unplanned absenteeism, respiratory illnesses including Covid-19, severe illnesses and deaths. Two additional trials by the Max Planck Institute in Germany of a TB vaccine candidate, VPM1002, are in the works.
Inovo Pharmaceuticals, Coalition for Epidemic Preparedness Innovations (Cepi): INO-4800
Type: Vaccine
Status: Experimental
Early results: 3-6 months
DNA plasmid vaccine delivered into the skin via a patch-style electroporation device. A clinical trial launched on April 3 could yield preliminary data by late summer, according to the company, which has said it can manufacture one million doses by year-end for additional trials and emergency use.
University of Asrhus, Denmark: Camostat mesylate
Type: Drug
Status: Repurposed
Early results: 6-12 months
Protease inhibitor licensed in Japan and South Korea to treat chronic pancreatitis. In vitro experiments found it blocks a mechanism Sars-Cov-2 uses to enter human cells. As of early April, an estimated 180 Covid-19 patients aged 18-110 were being recruited at nine locations in Denmark for a phase 2a trial that will examine 30-day changes in disease severity and mortality, with results expected by December 2020. The University of Tokyo also announced plans for a trial of camostat mesylate and a related drug, nafamostat mesylate, starting April 2020.
Inflarx: IFX-1
Type: Drug
Status: Experimental
Early results: 6-12 months
Monoclonal antibody targeting complement activation product C5a. Designed to block a mechanism of inflammation, the drug is also in clinical trials for Hidradenitis Suppurativa, ANCA-associated vasculitis and Pyoderma Gangraenosum. In early April, a trial in the Netherlands launched to test IFX-1 in patients with severe Covid-19 pneumonia, with preliminary results expected in late October 2020.
Cansino Biological Inc/Beijing Institute of Biotechnology: AD5-nCov
Type: Vaccine
Status: Experimental
Early results: 6-12 months
Non-replicating viral vector. A single-centre phase 1 trial with 108 subjects aged 18-60 in Wuhan, China, started in March to test the safety and immune responses generated by a recombinant vaccine that uses another respiratory virus, adenovirus, as a vector. On April 12, a randomised controlled phase 2 trial with 500 participants launched to test varying doses against placebo. Phase 1 completion is in late December 2020, and phase 2 results are expected in January 2021.
Imperial College London: Aspirin, Clopidogrel, Rivaroxaban, Atorvastatin, Omeprazole
Type: Drug
Early results: 9-12 months.
Trial of cardioprotective drugs to prevent direct damage to the heart muscle that appears to drive the severity of Covid-19 in certain patients as well as their likelihood of needing invasive critical care. The trial will include over 3,000 patients in the UK, with a completion date of March 30, 2021.
University of Oxford: ChAdOx1
Type: Vaccine
Status: Experimental
Early results: 12-18 months
Non-replicating chimpanzee adenovirus vector. Phase 1/2 trial with 510 subjects aged 18-55 at four centres in the UK. The trial will test safety and immunogenicity of one or two doses of the vaccine, and is expected to be completed in May 2021.
Serology/Antibody Testing
Type: Testing
Status: Experimental
Early results: 0-12 months
Governments and academic groups have started to test blood for antibodies indicating that a person has been exposed to the new virus, with or without showing symptoms. The presence of antibodies indicates past infection, but separate, ongoing research is needed to know what type and concentration of virus-neutralising antibodies protect against a new infection, whether all infections produce a full antibody response, and how long protection might last.
Wide serology testing for antibodies will soon provide a broader understanding of the scope and dynamics of the pandemic, help identify which recovered patients may have some immunity to reinfection and for how long, and also help identify the neutralising antibodies that could become templates for monoclonal antibody therapies, as well as models for desired responses from a vaccine candidate. Data from serology testing are expected to begin appearing within weeks.
Caveats
Early data on Covid-19 patients in China suggests that most develop varying amounts of antibodies in response to infection. One pre-publication report analysed plasma from 175 patients and found a sign of inflammation correlated with higher antibody titers and that younger patients were less likely to produce large amounts of antibodies.
Experts think instances of ‘reinfection’ in recovered patients are more likely relapses in patients whose bodies had not cleared the virus. Data is still lacking on whether mild or symptomless infections generate mea ningful antibody responses or protection.
Christine Soares
Medical Editor, Reuters
