Explore Reuters in-depth graphic: Coronavirus outbreak – The lifeline pipeline
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. While a safe, effective vaccine is still more than a year away, researchers are rushing to repurpose existing drugs and non-drug therapies as well as testing promising experimental drugs that were already in clinical trials. Reuters provided an in-depth graphic offering a look at some of the drugs, vaccines and other therapies in development.
https://www.reutersagency.com/en/reuters-best/explore-reuters-in-depth-graphic-coronavirus-outbreak-the-lifeline-pipeline/
The lifeline pipeline
By Christine Soares
Updated: September 10, 2020
Updates every Thursday
As much of the world emerged from lockdowns and stay-at-home orders, the spread of the new coronavirus, SARS-CoV-2, roared back at a record pace in the United States, Brazil, India and elsewhere, underscoring the urgent need for treatments and vaccines, even if the threat has lessened for now in much of Europe and Asia. The virus that was first detected in China late last year has now touched nearly every corner of the globe. As of September 16, 29.6 million had been infected and 935,000 killed by COVID-19, the disease caused by the virus.
While the race to produce safe, effective vaccines is moving at unprecedented speed with over 150 in development and some two dozen candidates already being tested in people as of July, there are no guarantees any will be successful or widely available any time soon. Meanwhile, researchers are rushing to repurpose existing drugs in an attempt to alter the course of severe COVID-19, as well as testing experimental treatments that were either already in clinical trials for other conditions or designed specifically to tackle this new illness.
Even moderately effective therapies or combinations could dramatically reduce the crushing demand on hospitals and intensive care units and the alarming toll the disease takes on the most vulnerable patients, changing the nature of the risk the new pathogen represents to populations and healthcare systems.
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Here are some of the most promising drugs, vaccines and other therapies in development to fight this global health crisis:
Antiviral drug given by infusion previously failed as an Ebola treatment but showed promise against certain coronaviruses in animal studies. In the first large, randomized COVID-19 trial, remdesivir led to a statistically significant reduction in recovery time of hospitalized patients compared with a placebo, demonstrating that it does impact the virus. Based on that data, the FDA issued an emergency use authorization for the drug despite mixed results from other smaller studies. More than a dozen trials underway in China, Europe and the United States with with positive results starting to emerge.
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Monoclonal antibodies based on virus-neutralizing antibodies isolated from recovered COVID-19 patients represent a class of therapies and potential prophylactics that could complete human testing and be manufactured in large volumes fairly quickly. Since early in the pandemic, researchers around the world have been racing to identify natural antibodies that can home-in on the SARS-CoV-2 virus, especially its "spike" protein, and disable its ability to infect cells. Dozens of groups are working on optimizing candidate monoclonal antibodies targeting the virus and on June 1, a team from Eli Lilly and AbCellera Biologics was the first to announce the start of clinical trials. AstraZeneca announced the start of a clinical trial in late August.
CAVEATS
Protection could be moderate, and these biologic therapies may be most effective in early stages of infection or when used in a "cocktail" with other SARS-CoV-2-targeted monoclonal antibodies or with small-molecule-based drugs.
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Regeneron launched a phase I/II trial in early June to test a cocktail of two antibodies, REGN10933 and REGN10987, that target different parts of the virus "spike" protein. In preclinical work, this approach averted the evolution of viral resistance to the antibodies, company researchers reported. The initial trial has an “adaptive” design and could quickly move from dozens of patients to eventually include thousands, the company's chief scientific officer told Reuters. In August, Regeneron partnered with Roche. The companies will fund and run ongoing late-stage Phase 3 prevention and earlier-stage Phase 1 healthy volunteer safety studies, as well as additional studies to evaluate REGN-COV2 in treating or preventing COVID-19.
CAVEATS
The initial trials will include outpatients and hospital inpatients with mild or moderate illness. The company has said it has plans to also test the REGN-COV2 combination as pre- or post-exposure prophylaxis.
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Lilly and partner AbCellera will test their monoclonal antibody therapy, which is also called LY3819253, in an initial U.S. safety trial in 40 hospitalized Covid-19 patients who don't require a ventilator and have not received treatment with convalescent plasma. The mid-stage trial data is expected in the fourth quarter. A phase 3 trial in nursing homes, with 2,400 participants, was announced in August.
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Antiviral combination used to treat and prevent HIV infections. More than 20 trials around the world are testing the therapy as a COVID-19 treatment or for post-exposure prevention for those with high-risk close contact with infected people.
CAVEATS
One randomized controlled trial in China found no differences in viral load or 28-day mortality among 199 patients, according to results published in March. Median time to clinical improvement was one day shorter in patients taking the drug. However, the same doctors at Jinyintan Hospital in Wuhan said in April that they believe Kaletra, as well as a second drug, bismuth potassium citrate, helped some of the COVID-19 patients they treated.
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Monoclonal antibody approved for rheumatoid arthritis and also used to treat a dangerous overreaction of the immune system called a "cytokine storm" in cancer patients receiving a type of therapy that can trigger that response. COVID-19 triggers a similar response in some patients who have fared poorly. Actemra targets interleukin-6 (IL-6), which is believed to play a role in inflammation.
CAVEATS
Registered trials in China, Europe and the United States are testing it on COVID-19 patients alone or in comparison to other therapies, but as of late July, results were not promising.
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Monoclonal antibody approved for rheumatoid arthritis that targets (IL-6). Early results announced in late April suggested a benefit in the most critically ill patients, however a U.S. phase 3 trial of the drug's effect on the cytokine storm immune response was halted in July for lack of efficacy. In late August, the companies dropped further studies of the drug after trials outside the U.S. showed adverse effects, including pneumonia.
CAVEATS
Based on review of early data showing little benefit for patients who were severely ill but not in critical condition, the companies announced they would continue the trial only in critical patients.
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From a class of drugs known as JAK inhibitors, Jakavi is approved to treat the rare bone marrow cancers myelofibrosis and polycythemia vera and is in late-stage development as a cream for atopic dermatitis. Trials in Canada and Mexico tested the drug in COVID-19 patients with severe pneumonia associated with the cytokine storm immune response. Preliminary results published in June showed that 12 of 14 patients with high inflammation experienced a 25% reduction in inflammation score by day 7 of treatment. A larger phase 2 trial is underway.
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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. A phase 2a trial launched in early April by Aarhus University will examine 30-day changes in disease severity and mortality, with results expected by December 2020. The University of Tokyo also plans a trial of camostat mesylate and a related drug, nafamostat mesylate. A Yale trial in outpatients who test positive for SARS-CoV-2 will look at whether the drug keeps viral loads low, which could help prevent mild illness from becoming severe. That could also make it a good prophylactic. A long safety track record adds to this drug's appeal.
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A map of the virus' interactions inside the human body flagged plitidepsin among several compounds that block a key human protein it needs to infect cells. Aplidin, a cancer therapy approved in Australia, had already shown activity against a different coronavirus in lab studies and was about to enter COVID-19 trials in Spain when the protein-mapping study supporting its potential was published in late April.
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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 the need for mechanical ventilation. Preliminary results from the trial are expected in September 2020.
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An old malaria drug that also treats lupus and rheumatoid arthritis is believed to have antiviral as well as anti-inflammatory activity. Blocked the novel coronavirus' (SARS-CoV-2) entry into cells in an in-vitro experiment. In one small French study, some COVID-19 patients showed improvement but there was no way to know if the drug was the reason. Subsequent studies have found little benefit in patients treated with the drug. The World Health Organization expects to make safety findings public by mid-June, but the U.S. Food and Drug Administration has revoked the emergency use authorization that allowed doctors to treat COVID patients with the drug outside of clinical trials.
CAVEATS
Health experts caution it should never be used without a prescription and could lead to dangerous side effects on the heart. Dozens of clinical trials to assess benefits to COVID patients are ongoing, but several major trials were halted following a WHO safety warning in late May. A planned international trial of the drug as a prophylactic for health workers was also suspended on safety concerns.
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Blood plasma from recovered COVID-19 patients is transfused into patients who are currently ill, in the hope that freshly-made antibodies 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 of a benefit. Results published in August from a large study found the treatment does reduce risk of death in COVID-19 patients.
CAVEATS
Studies suggest so far that the treatment is most effective when used early in the course of disease.
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NKG2D receptor for the immune system's natural killer (NK) cells that play a major role attacking foreign invaders like cancer or viruses, paired with the ACE-2 receptor that the coronavirus uses to enter human cells. A multicenter 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.
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Monoclonal antibody designed to block a mechanism of inflammation. In early April, a trial in the Netherlands launched to test IFX-1 in patients with severe COVID-19 pneumonia.Interim results from the first 30 patients showed a trend toward lower all-cause mortality, fewer pulmonary embolisms and less kidney impairment in treated patients.
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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 more than 3,000 patients in the United Kingdom, with a completion date of March 30, 2021.
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Health policy experts say the United States must dramatically increase the availability of tests for the coronavirus if it is to safely reopen its economy. From the start, laboratory-based diagnostic testing has been hampered by shortages of needed materials such as swabs to collect samples and chemical reagents. U.S. regulators have moved speedily to authorize many new commercial tests, but concerns still remain about their accuracy, and some policymakers say entirely new testing technologies need to be developed to fully contain the virus. At present, two types of diagnostic test are available: one looks for the virus' genetic material, or RNA, and the other looks for viral proteins known as antigens. In general, antigen tests have lower accuracy rates than RNA testing.
CAVEATS
Without additional analysis, neither RNA nor antigen tests can tell the difference between active virus, which could infect others, and "dead" viral particles that are no longer contagious. Researchers believe this may explain some cases of recovered patients testing positive for extended periods.
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Authorized for use by U.S. regulators in March, Roche says it is currently shipping around 8 million tests per month. It requires a sample taken by nasal swab be sent back to a lab for analysis to detect viral RNA. Roche says studies show it can detect very low levels of the virus with 95% accuracy.
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Approved in late March, Abbott’s rapid, point-of-care molecular diagnostic test can provide results on site to patients within minutes. As of May 4, Abbott said it is producing 50,000 of these tests per day, and plans to ramp up to 2 million by June.
CAVEATS
The U.S. FDA issued an alert in May cautioning the public about the test's "potential inaccurate results."
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Authorized for use in early May, Quidel said this antigen test picks up around 80% of COVID-19 cases.
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It takes about 30 minutes to get a result with Fujirebio's palm-sized antigen test kit, compared with four to six hours for a standard laboratory process known as PCR, according to Japan's health Ministry. Fujirebio can produce 200,000 kits per week, roughly on par with the number of RNA-based diagnostic tests conducted in April in Japan.
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Governments and academic groups have started serosurveys: testing blood for antibodies indicating that a person had been infected by the virus whether or not they had symptoms.
But separate, ongoing research is needed to know what type of antibody neutralizes the virus and what concentration of these in the bloodstream protects against a new infection, as well as whether all infections produce a full antibody response, and how long any protection might last.
Antibody tests take small samples of patients' blood and can be conducted in labs or with on-site tests that provide results in minutes. The FDA tightened rules on serological test developers after a proliferation of unauthorized tests raised questions about their reliability. Independent academic groups are also testing the individual tests to assess their accuracy.
But separate, ongoing research is needed to know what type of antibody neutralizes the virus and what concentration of these in the bloodstream protects against a new infection, as well as whether all infections produce a full antibody response, and how long any protection might last.
Antibody tests take small samples of patients' blood and can be conducted in labs or with on-site tests that provide results in minutes. The FDA tightened rules on serological test developers after a proliferation of unauthorized tests raised questions about their reliability. Independent academic groups are also testing the individual tests to assess their accuracy.
CAVEATS
Data on COVID-19 patients suggests that most develop varying amounts of antibodies in response to infection, but how long they last and how much protection they offer has been unclear. Three cases reported in August of documented re-infection months after recovering from a bout with COVID-19 suggest that protection can be incomplete but subsequent infections might produce mild or no illness.
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Researchers at the University of Washington School of Medicine say the test, which Abbott launched in April, has a specificity of 99.9% and a sensitivity of 100%, suggesting very few false positives and no false negatives. Abbott has already shipped more than 10 million antibody tests to hospitals and labs.
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Roche says the test, which runs on its widely available cobas e analyzer, has 98% specificity and 100% sensitivity in detecting antibodies 14 days after an infection is diagnosed. The company began providing millions of tests in Europe in May and says it can ramp up to supply larger quantities thereafter.
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Formerly known as ChAdOx1, this vaccine candidate originally developed at Oxford University is based on a non-replicating chimpanzee adenovirus vector. Human trials on more than 1,000 volunteers began in April. Data released in May on tests in six rhesus macaques showed that when vaccinated monkeys were challenged with the virus, the vaccine appeared to prevent damage to the lungs and kept the virus from making copies of itself there, but the virus was still actively replicating in the nose, meaning they were not entirely protected from infection. In September, late-stage human studies were paused while researchers assessed a single case of spinal inflammation in a trial volunteer to see if it was related to the vaccine.
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Based on messenger RNA encoding viral proteins, this candidate started phase 3 trials in late July. Pfizer already collaborates with BioNTech to develop mRNA-based vaccines for influenza. Pfizer has said it hopes to receive emergency authorization from the U.S. Food and Drug Administration for the new vaccine as early as October, and could distribute up to 20 million doses by the end of 2020, with an eye toward producing hundreds of millions of doses next year.
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In mid-April, two of the world's largest vaccine makers announced they would join forces to create and test six candidates built on technologies already proven in flu vaccines. In all candidates, Sanofi's recombinant S-protein COVID-19 antigen will get a boost from GSK's AS03 adjuvant. Scientists and public health experts are already warning that it could be tricky to induce a strong, effective immune response to the SARS-CoV-2 virus, particularly in the elderly and others with weakened immune systems, so the adjuvant enhancement could help. The resulting vaccine might also require just one dose instead of two, which could stretch supplies. In late July, Sanofi announced an agreement to supply the U.S. government with 100 million vaccine doses, worth up to $2.1 billion, and an option to supply an additional 500 million doses.
CAVEATS
The AS03 adjuvant was in GSK's 2009 Pandemrix flu vaccine used in Europe. But only a handful of adjuvanted vaccines are licensed in the U.S., and none containing AS03. The exception is a flu vaccine approved in 2013 and stockpiled by the U.S. for use in the event of an H5N1 avian flu pandemic.
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Based on a candidate developed with Beth Israel Deaconess Medical Center in Boston, this vaccine uses an engineered common cold virus (adenovirus 26) to deliver genetic instructions for making SARS-CoV-2 antigen proteins. AD26 is the same platform the company is testing in vaccines against Ebola, HIV, respiratory syncytial virus and Zika. The U.S. government has already pledged at least a half-billion dollars to support development and testing of the coronavirus vaccine candidate. Clinical trials began in July; phase 3 trials in up to 60,000 volunteers are expected to start in September.
CAVEATS
There are longstanding concerns that using common viruses like adenoviruses as a vaccine carrier, or vector, might lead the immune systems of people already exposed to the vector to attack the vaccine, reducing its efficacy. Several candidate vaccines against the novel coronavirus employ viral vectors and the solution to vector immunity is often to increase the vaccine dose.
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RNA vaccine made with messenger-RNA (mRNA) encoding the spike protein on the surface of the new coronavirus (SARS-CoV-2) and delivered via a lipid nanoparticle. Data released in May showed that eight subjects in a phase 1 trial at three locations in the United States produced immune responses and had no serious adverse reactions. The vaccine started large, late-stage trials at the end of July and will get FDA "fast-track" review.
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This mRNA candidate uses a platform already showing promise in human trials of a rabies vaccine, and in preclinical development for flu and other viruses. In May, the German biotech announced that its lead coronavirus vaccine candidate produced strong and balanced immune responses in animal tests. Human testing began in June.
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Based on a "vector," or vehicle, originally developed at the Pasteur Institute and licensed to Themis Biosciences, this vaccine uses a genetically engineered version of a weakened measles virus that incorporates instructions for making SARS-CoV-2 “antigen” proteins to induce an immune response. Vaccines like this one, based on a vector that replicates inside human cells, typically induce strong immune responses. Merck acquired Themis in late May, saying it will be moving quickly with this candidate. In September, the company said it expects to start vaccinating volunteers "fairly soon."
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This vaccine developed by non-profit IAVI also uses an engineered (recombinant) version of a weakened virus, vesicular stomatitis virus (VSV), as a vector to carry genetic instructions for making SARS-CoV-2 antigen proteins. It's the same technology in Merck’s Ebola vaccine ERVEBO, recently approved by the European Commission and the U.S. Food & Drug Administration. Human tests are expected to begin sometime in late 2020.
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Non-replicating viral vector. A single-center phase 1 trial with 108 subjects aged 18 to 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, to deliver the vaccine material. On April 12, a randomized controlled phase 2 trial with 500 participants launched to test varying doses against placebo. Phase 1 completion is expected in late December 2020, and phase 2 results are expected in January 2021.
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Novavax said its Matrix-M adjuvant would be used with the vaccine candidate - NVX-CoV2373 - to enhance immune responses. Trial in 130 adults is expected to begin in mid-May with with preliminary immunogenicity and safety results in July, according to the company.
CAVEATS
Strong immunogenicity in animal tests, but might require two doses in humans, which would limit supply.
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DNA plasmid vaccine delivered through the skin via a patch-style device using a brief low-voltage electronic pulse to induce cell membranes to open, making them more receptive, in theory, to accepting the vaccine's genetic material. A clinical trial launched on April 3 could yield preliminary data by late summer, according to the company, which has said it can manufacture 1 million doses by year-end for additional trials and emergency use.
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Engineered minigenes encoding viral antigens; lentiviral vector designed to infect dendritic and T cells - key components of the immune system - to induce immunity. The trial in 100 adults in Shenzen, China, was still recruiting as of July 31, 2020.
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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 defenses in health workers and the elderly reduces unplanned absenteeism, respiratory illnesses including COVID-19, severe illnesses and deaths. In a small trial in the United Arab Emirates, none of the 71 hospital staff who received a BCG booster shot in early March had been infected with the virus by late June, compared with 18 of 201 staff who did not receive the vaccine and tested COVID-19 positive.
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Design and illustration by Maryanne Murray
https://graphics.reuters.com/HEALTH-CORONAVIRUS/yxmvjq
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