Researchers Around the Globe Are Racing To Discover and Create COVID-19 'Game Changers'
None have yet emerged that can clearly stem the tide of the ongoing pandemic.
On March 19, 2020, President Trump touted the anti-malaria drug chloroquine as a possible "game changer" in the fight against the coronavirus pandemic. However, at the same press conference, Food and Drug Administration (FDA) commissioner Stephen Hahn cautioned that what "is important is not to provide false hope." Now almost a month later, do any therapeutic pandemic game changers look likely to emerge soon?
First, the good news. Research on therapies for coronavirus infections is ramping up at a blistering pace. Genetic Engineering & Biotechnology News reports that at least 161 treatments and vaccines for COVID-19 are proposed or are in development. As of April 9, the Milken Institute's COVID-19 Treatment and Vaccine Tracker has identified 243 potential coronavirus treatments in the research pipeline. The U.S. National Library of Medicine's ClinicalTrials.gov site lists 524 studies that have been proposed or are already being undertaken to find ameliorative treatment regimens, therapeutics, and vaccines for COVID-19.
Now let's turn to the not so great news.
Hydroxychloroquine & chloroquine
Based on largely anecdotal evidence, the FDA on March 30 issued an emergency use authorization for chloroquine and the related anti-malarial hydroxychloroquine as experimental treatments for hospitalized COVID-19 patients. ClinicalTrials.gov lists 58 studies worldwide testing the efficacy of hydroxychloroquine against COVID-19 with 21 taking place in the United States. The site also identifies 13 studies worldwide on chloroquine with 2 studies in the U.S. A quick review of the clinical trials finds that most of them have yet to be launched and that almost none will be completed before this coming fall.
In the meantime, evidence from the small chloroquine and hydroxychloroquine studies that have been completed unfortunately do not suggest that treatments using the two anti-malarial are game changers. The initial optimism about the anti-malarials was fueled by the results of a small non-randomized French study that reported the elimination of coronavirus in 20 patients after six days of treatments combining hydroxychloroquine and the antibiotic azithromycin. However, the scientific society that publishes the journal in which the French study appeared issued a statement in April that the study did not meet its expected evidentiary standards.
Some support for the idea that hydroxychloroquine might be an effective treatment was reported by a Chinese study that randomly assigned hydroxychloroquine to half a cohort of 62 COVID-19 patients. After five days "the body temperature recovery time and the cough remission time were significantly shortened in the HCQ [hydroxychloroquine] treatment group" reported the researchers.
Contrariwise, a study at the Shanghai Public Health Clinical Center in which 30 COVID-19 patients were randomly assigned standard care or treatment with hydroxychloroquine found essentially no differences between the groups. Another randomized controlled trial of 150 hospitalized COVID-19 patients just released by Chinese researchers also found no difference in the rate of viral load reduction or symptom alleviation between the group treated with hydroxychloroquine and the one that had not been. The researchers do note that perhaps future studies in which COVID-19 patients are treated earlier in the course of their infections could possibly turn out to be more than marginally therapeutic. In any case, some of the several dozen other studies might eventually show some significant efficacy for the two anti-malarials in treating COVID-19, but the early indications are not promising.
Another strategy to defeat the coronavirus is to identify and deploy an anti-viral compound as a pandemic game changer. One of the more hopeful prospects is the antiviral compound remdesivir, manufactured by the biotech company Gilead. Researchers reported in 2018 that it potently inhibited replication of a variety of coronaviruses, including those that cause SARS and MERS in in vitro and mouse model tests. ClinicalTrials.gov lists 10 trials (two Chinese trials were just suspended) in which the intravenously delivered drug is being tested to treat COVID-19 patients.
An April 10 New England Journal of Medicine article reported clinical improvement in 36 of 53 patients hospitalized for severe COVID-19 who were treated with compassionate-use remdesivir. However, the lack of a control group means no hard conclusions can be drawn from these results. The earliest results from randomized controlled trials is not expected until the end of May.
Another anti-viral being repurposed as a possible COVID-19 treatment is the anti-influenza drug favipiravir. ClinicalTrials.gov lists five trials using it, some in conjunction with other therapies. A Chinese study that evenly divided 240 COVID-19 patients into two cohorts compared the effects of the antivirals favipiravir and arbidol on the course of their infections. While favipiravir relieved the patients' fevers and coughing faster, a week later there was no significant difference in the clinical recovery rate of the patients. The results from a couple of the other trials should be coming in around June.
Hopes are high for the broad-spectrum anti-viral compound EIDD-2801, developed by researchers at the biotech company Ridgeback Biotherapeutics and Emory University. The researchers report that in laboratory studies the compound powerfully inhibits the replication of various coronaviruses, seasonal and bird influenza, respiratory syncytial virus, chikungunya virus, Ebola virus, Venezuelan equine encephalitis virus, and Eastern equine encephalitis virus. On April 10, the United Kingdom's Medicines and Healthcare products Regulatory Agency gave the go-ahead for the company to begin a phase I clinical trial for the orally available anti-viral.
Antibodies are proteins produced by the immune system that attack invading viruses and bacteria. Biotech companies have developed a number of antibody therapies to treat autoimmune disorders and cancers. There are various techniques for identifying and then producing human antibodies as therapies. However, very few antibody therapies have been developed to treat or prevent infectious diseases.
An old form of treatment that is being pursued by a number of drug companies is to infuse the antibody-laden plasma from folks who have recovered from COVID-19 into patients with the goal of fending off the infection long enough for them to produce their own defensive antibodies. In late March, the Journal of the American Medical Association reported the results of a small Chinese uncontrolled case study in which convalescent plasma was transfused into five patients on ventilators. All five improved and three were discharged from the hospital. Now ClinicalTrials.gov lists 22 trials using convalescent plasma to treat COVID-19.
One of the more dangerous complications of COVID-19 is the damage that excessive inflammation can cause as the body mounts its immune response to the coronavirus. In a small Chinese study the anti-cancer antibody therapy Actemra helped tame this effect in 20 patients, eliminating their fevers and clearing their lungs. While several companies are racing to isolate specific COVID-19 antibodies from the plasma of recovered patients with the aim of producing coronavirus therapeutics, there are no clinical trials for them yet scheduled.
According to the World Health Organization there are 70 candidate coronavirus vaccines in development now, but only three of them are currently in human clinical trials. Researchers around the world are cooking up vaccines using a wide variety of recipes including DNA, RNA, live attenuated, and recombinant vaccines. Microsoft co-founder and philanthropist Bill Gates has declared that his foundation is planning to pick the seven likeliest candidates and begin building immediately afterwards the manufacturing capacity for millions of doses of each them, with the hope that one or two of them will prove effective. So far, no vaccine has ever been developed and deployed to prevent any coronavirus infection in humans.
The search for COVID-19 game changers is urgent and moving fast, but none have yet emerged that can clearly stem the tide of the ongoing pandemic.