The interim results of the World Health Organization’s massive Solidarity Therapeutics Trial are in — and they don’t bode well for remdesivir, the antiviral drug that for months was touted as a moderately effective treatment for Covid-19, and three other drugs.
The study, which involved more than 11,300 people across 30 countries and is currently undergoing peer review, examined the efficacy of four repurposed antivirals — remdesivir, hydroxychloroquine, lopinavir-ritonavir, and interferon. Patients prescribed any of the four, the results show, weren’t any likelier to survive than those who weren’t. Neither were their hospital stays any shorter.
We already knew this much, more or less, about hydroxychloroquine and lopinavir, in part due to the release of the results of the RECOVERY trial, a study similarly large but conducted only in the United Kingdom. Both treatments were dropped from the Solidarity trial roster shortly thereafter.
But for remdesivir and interferon, the conclusion that neither drug reduces mortality carries more weight. When put to the test in smaller studies, remdesivir appeared to lead to earlier hospital discharges and an overall shorter disease course for some patients. It is notable that Gilead, the company behind remdesivir, cited this particularly promising outcome in justifying the treatment’s $3,120 price tag.
As for interferon, a protein that alerts the immune system whenever an intruder is on sight, researchers had high hopes that interferon-based therapies might do more to help patients fend off severe and life-threatening symptoms. This hope was founded in part on earlier findings that the Covid-19 virus, SARS-CoV-2, actively dampens our interferon response as a means of weaseling into our cellular machinery. It so follows that a load of synthetic interferons might shore up that critical yet compromised line of defense, though for this particular candidate that didn’t prove to be the case.
While not many interferon-based therapies have made it very far down the research-to-market pipeline, the same can’t be said for remdesivir. Not only was it authorized for emergency use by the U.S. Food and Drug Administration in May and included in the treatment regimens of public figures as high-profile as the president of the United States himself, earlier this month a six-month supply of the drug was also sold to the European Commission for $1 billion.
In a statement released shortly after the Solidarity trial results went live, Gilead expressed concern over “the limitations of the trial design,” which per their analysis “prioritized broad access” over methodological rigor. They fail to mention that one of their own studies on remdesivir — conducted in China and still heavily cited to this day — was prematurely terminated, ostensibly due to low patient enrollment.
Many consider the randomized controlled trial to be an essential — if not inviolable — component of drug discovery and approval, even in times of crisis when stakes seem too high to deprive the selected control group of a potentially beneficial drug. Broad though the findings of the Solidarity trial may be, they give us the most accurate representation — so quickly as to nearly be in real time — yet of how these drugs are working around the world today, and how they would work if they were to be manufactured and distributed globally.
The answer, unfortunately, is not so well, but that knowledge in and of itself is useful. It will be far more difficult to obtain for treatments like convalescent sera and monoclonal antibodies, which due to logistical complications are difficult to make, much less deploy, on a large scale.
Not for nothing have both convalescent sera and monoclonal antibodies received emergency use authorizations (EUAs) in the United States, despite a lack of robust scientific evidence proving their efficacy. This doesn’t necessarily undermine the necessity of EUAs, but it does raise the question of whether their impact on the health and safety of actual patients nets positive or negative. Without large-scale clinical trials and strict regulatory standards, it becomes difficult to tell whether EUAs serve a purpose of clinical or political expediency — a boundary too dangerous to cross, especially when so many lives are on the line.
It may be the case that using antivirals to treat late-stage Covid-19, which is associated with the hyperinflammatory symptoms that make the disease a matter of life or death for some, is something of a nonstarter. At that point, patients require interventions that address the onerous and occasionally lethal consequences of viral infection, rather than the virus itself. This may be the reason why treatments like anticoagulants and corticosteroids like dexamethasone are now more associated with survivability than their antiviral counterparts.
In any case, the results of the WHO Solidarity trial form a valuable contribution to our ongoing search for Covid-19 treatments. They emphasize the importance of conducting large-scale, randomized controlled drug trials even amidst a fast-developing global health crisis.