In the hope of a coronavirus treatment
Chloroquine, remdesivir and other potential Covid-19 treatments explainedValentina Spiridonova
An antiviral originally designed to tackle Ebola. An anti-malarial treatment dating back to World War II. A drug combo already used against HIV. A molecule involved in regulating inflammation in the body tested on marmosets. You might ask what all of these drugs have in common? Well, according to the World Health Organisation, these compounds have the highest likelihood of working against Covid-19. Thus, they are all on focus on WHO's megatrial, called SOLIDARITY.
Given the speed at which the infection is spreading, developing new drugs from scratch presents a challenge as it might take years not only to design, but also test. Medical experts are hence turning to repurposing existing drugs already approved for other diseases to combat the pandemic. Another category consists of unapproved drugs that have performed well in animal studies with the other two deadly coronaviruses, which cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). But scientists count on them all since they can not only prove to be efficient in slowing or killing the novel coronavirus, called SARS-CoV-2 or Covid-19, but could also save the lives of already severely ill patients and might be given prophylactically, to protect health care workers and others most at-risk of infection.
As we already announced in a previous article, these four most promising therapies are remdesivir, a combo of chloroquine and hydroxychloroquine, as well as lopinavir and ritonavir and a combination of the latter plus interferon-beta, an immune system messenger that can help cripple viruses. These medicines will be also tested in an add-on trial in Europe, named Discovery, that will follow WHO’s example and was initiated by the French National Research Institute for Medical Research (INSERM). The only exception would be chloroquine.
So why does the scientific community believe that these are the drugs that have the highest likelihood of working against Covid-19 besides the fact that they have most safety data from previous use and are potentially available in supplies sufficient to treat substantial numbers of patients? We will try to explain, citing official scientific sources.
Remdesivir was originally designed to tackle Ebola by inhibiting an enzyme called RNA polymerase that’s used by many viruses to replicate, though it never succeeded in that indication. In a 2017 Science Translational Medicine study, however, scientists found the medication could also kill SARS and MERS - two other coronaviruses that caused deadly outbreaks in the 21st century - at the very least in lab dishes.
Since the early days of the current coronavirus outbreak, Gilead Sciences’ experimental antiviral drug remdesivir has been hailed as a leading hope. In early February, two months after the new pathogen emerged, WHO's head of organisation’s Covid-19 mission in China - Bruce Aylward even called remdesivir the “most promising” treatment. Hopes in the drug shot up further after a case report in the New England Journal of Medicine (NEJM) showed that the first US patient was given remdesivir when his condition worsened and he improved in just a day. A Californian patient who received remdesivir - and who doctors thought might not survive - recovered as well.
Interests in the drug are shared across the Pacific, too. Chinese scientists have already initiated two clinical trials of remdesivir in mild to moderate and severe Covid-19 patients, with early results expected in just few weeks. The National Institutes of Health’s National Institute of Allergy and Infectious Diseases is running a study, and Gilead itself is also testing the drug’s anti-Covid-19 effect in two clinical trials.
“Enrollment in clinical trials is the primary way to access remdesivir to generate critical data that inform the appropriate use of this investigational medicine,” Gilead said in its Sunday statement.
But because remdesivir is not FDA-approved for general use, only patients with the most severe, and late-stage, disease, qualify for its use in clinical trials, Thompson told Science.
Chloroquine and hydroxychloroquine
Things are getting more complicated here.
Hydroxychloroquine and chloroquine are oral prescription drugs that have been used for treatment of malaria and certain inflammatory conditions. Chloroquine, in particular, is a derivative of quinine, which French chemists in 1820 isolated from the bark of the cinchona tree found in South America, employing it as a treatment for fevers, according to the Swiss-based organisation, Medicines for Malaria Venture. The synthetic chloroquine, however, was created almost a century later, in 1934 as part of a class of anti-malarials, and along with DDT became "the two principal weapons in WHO's global eradication malaria campaign" following World War II.
Hydroxychloroquine, on the other hand, is what's known as an analog of chloroquine, meaning the two have similar structures but different chemical and biological properties. The former is considered the less toxic derivative, according to studies.
It is currently used for treatment of rheumatoid arthritis, systemic lupus erythematosus and the blood disorder porphyria cutanea tarda.
Citing a study, documented in the journal Bioscience Trends this month, US's Centers for Disease Control and Prevention claims that chloroquine treatment of Covid-19 patients had clinical and virologic benefits versus a comparison group. It is thus considered a recommended antiviral for Covid-19 treatment in China, and several countries are recommending both drugs for hospitalised Covid-19 patients, the CDC adds even though the data underlying the claim have not been published in the study. There are claims that hydroxychloroquine also has in-vitro activity against SARS-CoV, SARS-CoV-2, and other coronaviruses, but is having relatively higher potency against SARS-CoV-2.
So far so good. Yet, the available data on these treatments are thin and results from Covid-19 patients are murky.
As the journal of the American Association for the Advancement of Science (AAAS) says, the two drugs work by decreasing the acidity in endosomes, compartments inside cells that they use to ingest outside material and that some viruses can coopt to enter a cell. But the main entryway for SARS-Cov-2 is a different one, using its so-called spike protein to attach to a receptor on the surface of human cells. Studies in cell culture have suggested chloroquines have some activity against SARS-CoV-2, but the doses needed are usually high - and could cause serious toxicities.
Encouraging cell study results with chloroquines against two other viral diseases, dengue and chikungunya, didn’t pan out in people in randomised clinical trials. And non-human primates infected with chikungunya did worse when given chloroquine.
“Researchers have tried this drug on virus after virus, and it never works out in humans. The dose needed is just too high,” says Susanne Herold, an expert on pulmonary infections at the University of Giessen, Germany.
Researchers in France have also published a study in which they treated 20 Covid-19 patients with hydroxychloroquine and compared their results to 16 who did not take the drug. They concluded that the drug significantly reduced viral load in nasal swabs. But it was not a randomised controlled trial and it didn’t report clinical outcomes.
Even worse, six patients dropped out of the trial from the group receiving the drug, and three of them ended up in intensive care and one died. These could be viewed as failures of the drug to work against the virus, Alfred Kim of the Washington University Lupus Clinic told Undark magazine.
The study has thus been heavily criticised by outside experts. For instance, infectious disease geneticist Gaetan Burgio of the Australian National University noted that statistically, weighing national responses to a pandemic on a study of 20 people was unwise, that the French study was not conducted with doctors and patients blind to the treatment, and that only a quarter of the placebo patients had their viral load measured.
CDC also noted that the small, non-randomised study "did not assess clinical benefit[s]" associated with the treatment; in other words, the study did not probe whether the treated patients were more likely to recover and survive their illness.
This combination drug, sold under the brand name Kaletra, was approved in the US in 2000 to treat HIV infections. Abbott Laboratories developed lopinavir specifically to inhibit the protease of HIV, an important enzyme that cleaves a long protein chain into peptides during the assembly of new viruses. And because lopinavir is quickly broken down in the human body by our own proteases, it is given with low levels of ritonavir, another protease inhibitor, that lets lopinavir persist longer.
The combination can inhibit the protease of other viruses as well, specifically coronaviruses. It has shown efficacy in marmosets infected with the MERS virus, and has also been tested in SARS and MERS patients, though results from those trials are ambiguous. The first trial with Covid-19, however, was not encouraging either.
A test in Chinese patients with severe Covid-19 disease found the 99 who received AbbVie Inc's Kaletra, fared no better than the 100 who received standard care.
A test in Chinese patients with severe Covid-19 disease found the 99 who received AbbVie Inc's Kaletra, a combination of lopinavir and ritonavir, fared no better than the 100 who received standard care. People who received the combination showed small gains in the time to clinical improvement and mortality at 28 days, but the differences were not statistically significant. People on the drugs also showed clinical improvement after a median of 15 days compared to 16 days with standard care, a difference the researchers characterised as "significant, albeit modest."
The treatment "was not associated with clinical improvement or mortality in seriously ill patients with Covid-19 different from that associated with standard care alone," concluded the team, led by Dr. Bin Cao of the National Clinical Research Center for Respiratory Diseases.
But the lopinavir-ritonavir combination produced more side effects, prompting the treatments to be halted in 13.8% of patients.
Ritonavir/lopinavir + interferon beta (IFN-β)
Still, the WHO will test not only the two antivirals, but them also combined with interferon-beta. Interferon beta, forms part of the lung’s natural defence system against viruses and was originally developed for patients with chronic obstructive pulmonary disorder, or COPD. Interferon beta has been also used to treat multiple sclerosis (MS) longer than any other disease-modifying therapy and molecule has also shown an effect in marmosets infected with MERS.
Back in February it was identified by the WHO as the only therapy in Phase-2 trials that can be inhaled, meaning patients can administer it themselves through a small battery-operated nebuliser. Meanwhile, a combination of the three drugs is now being tested in MERS patients in Saudi-Arabia in the first randomised controlled trial for that disease.
The effectiveness of the interferon treatment on Covid-19 is yet to be scientifically proven.
The design of the SOLIDARITY trial can change at any time. A global data safety monitoring board will look at interim results at regular intervals and decide whether any member of the quartet has a clear effect, or whether one can be dropped because it clearly does not. Several other drugs, including the influenza drug favipiravir, produced by Japan’s Toyama Chemical, may be added to the trial, but its not official yet.