The global effort to develop COVID-19 vaccines is a scientific triumph. However, the search for new forms of therapy for the disease is much less successful. More than a year and a half after the start of the pandemic, there are still few treatment options for COVID-19 – and the resources available appear to have only a modest impact on the course of the disease.
Vaccination rates may now be high enough in early Western countries to bring herd immunity within reach, but the need for real therapies remains great. Because the virus is raging in some countries with limited access to vaccines – and even where it is possible to vaccinate, some people just don’t want it. “The need for therapies for all stages of the disease is indeed greater than ever,” says Rachel Cohen, executive director of the Drugs for Neglected Diseases Initiative (DNDi), an organization committed to the development of new drugs for diseases historically ignored by pharmaceutical companies. “Never in the history of fighting a major infectious disease has there been a single set of tools like it is now.”
Intervene in time
New drugs could help people in the early stages of COVID-19 avoid hospitalization, “especially in places where intensive care and healthcare capacity are very limited,” says Cohen. They could also prevent people in hospital from dying after all.
New therapies could also be a crucial tool if SARS-CoV2 mutates to such an extent that it escapes the immune response, even in people who have been vaccinated. And there’s another reason to keep looking for new drugs: SARS-CoV2 is the third problematic coronavirus that has made the leap from animals to humans in the past 20 years. “This may not be the last such coronavirus we’ll see,” says Michael Diamond, a virologist at the Washington University School of Medicine.
The US government hopes the money can be used. In mid-June, she announced that Washington would allocate $ 3.2 billion to research and develop antiviral drugs for COVID-19 and future pandemic viruses. It’s only a fraction of the more than $ 10 billion the Trump administration spent on vaccine development on Operation Warp Speed, but the value is still “huge,” Cohen says. A number of other initiatives to promote the development of antiviral drugs are also underway.
There are currently only a handful of therapies available to treat COVID-19. For patients with the worst clinical picture, studies have shown that the steroid dexamethasone reduces the risk of death by a third by easing the rampant inflammatory response. Other therapies target the virus itself. Some companies have received emergency clearance for monoclonal antibodies. These lab-made antibodies work like natural antibodies: they bind to the virus and block it so that it cannot attack cells.
When given early, monoclonal antibodies or a combination of these therapies reduced the number of hospitalizations or deaths by 70-87% in people at high risk of severe symptoms or hospitalizations. These drugs work best in patients who are not yet seriously ill. However, Regeneron’s antibody combination – the therapy former US President Donald Trump received – also appears to help people who are already hospitalized but have not yet produced their own antibodies. In mid-June, researchers announced that a study of 9,000 people had reduced mortality in this group by 20%. This gain in life did not extend to people who had natural antibodies.
But antibody therapies also have drawbacks. They are expensive and must be given by infusion or injection. This makes it a poor option for many low and middle income countries. Additionally, they may not work as well against some outstanding variants. In fact, on June 25, the FDA suspended national distribution of Lilly’s antibody cocktail because two variants of SARS-CoV-2 that did not appear to respond to drugs were becoming increasingly common.
With antiviral drugs, which reduce the ability of the virus to replicate, the options are even fewer. Remdesivir is the only drug approved for the treatment of COVID-19, largely because it was one of the few candidates to have been tested for safety in humans at the time of the pandemic, giving it length in advance. But how well it works is still an open question. Some studies have shown that it shortens the duration of illness, while others suggest that it has little effect. The World Health Organization does not currently recommend its use.
The development of antiviral drugs has been delayed for a number of reasons. Until COVID-19, companies didn’t have much financial incentive to develop these therapies. Antiviral drugs only target ten viruses – half of them treat HIV. Chronic infections require longer treatments and therefore bring in more money. “Unless there is a clear market for a therapeutic agent, there is usually no investment in these types of drugs,” says John Bamforth, acting CEO of READDI, a private government collaboration at the University of North Carolina at Chapel Hill which was founded to develop new antiviral drugs.
There are also a number of scientific barriers. To inhibit replication, a drug must bind to an essential viral protein or enzyme and block its activity without harming the host cell. Unlike bacteria, viruses rely on the machinery of the cells that inhabit them to copy themselves, so they have relatively little protein. And even when researchers find an active ingredient that works, its effectiveness is usually short-lived as viruses are constantly changing.
Some researchers, including those at READDI, are working on drugs that target cellular proteins essential for viral replication. Most antiviral drugs only work against one virus. The hope is that these compounds will be effective against entire families of viruses. They would then also be less likely to lead to resistance.
But new therapies need more time to develop. That’s why the fastest way to market drugs is to reuse already approved active ingredients. They have already been tested for safety, and there are fewer regulatory barriers to approving a new use for an existing drug. DNDi is testing a number of existing drugs in a clinical trial called ANTI-VOC. The latest study is on the antiparasitic drug nitazoxanide combined with an inhaled steroid. âThe emerging consensus is that you need a strong antiviral or a combination of antivirals with different mechanisms of action, combined with some type of anti-inflammatory,â Cohen explains.
The US government’s Pandemic Antiviral Drugs Program aims to speed up testing of 19 drugs already in development. It will also allocate around $ 1 billion to launch a drug discovery program that will research substances that can treat not only SARS-CoV-2, but other viruses as well. The government also announced that it will purchase up to 1.7 million doses of Merck’s antiviral drug, molnupiravir, for $ 1.2 billion, pending regulatory approval. Researchers once planned for this drug to be used as a flu medicine, but when the pandemic hit, they had to change. The active ingredient has already passed phase 2 testing for COVID-19.
Access is uneven
More than 20 biotech and pharmaceutical companies have joined forces in the INTREPID alliance to advance 25 late-stage drug candidates targeting viral pathogens with the greatest pandemic risk, including coronaviruses. And the “COVID Moonshot” is an international consortium of scientists from academia, biotechnology, and the pharmaceutical industry who work on a pro bono or cost basis on the development of drugs that inhibit a certain SARS-CoV-2 enzyme. The project is based on crowdfunding and crowdsourcing. Anyone can submit a draft active ingredient and view drafts that have already been submitted. As of June 28, the project had collected 17,976 molecular designs and synthesized and tested nearly 1,500.
All these new initiatives may not bear fruit for a few years. But the hope is that we will be better prepared when the next pandemic breaks out. âWe have to stop this cycle of ignorance and panic that follows,â Cohen says. Great inequalities have emerged in the uptake of COVID-19 vaccines. In the US and UK, over 45% of the population has been vaccinated. In the Democratic Republic of the Congo and Chad, less than 0.1 percent of people have been vaccinated. And where immunization coverage is low, the virus can spread. âWe are seeing recurring crises in the Indian subcontinent, in Latin America and, in recent weeks, in Africa,â Cohen explains. These are places that urgently need new therapies, but she is concerned that not all newly developed treatments are reaching those countries just yet.
This is something READDI is thinking about. âIf we were to authorize a drug, we would probably include a global access clause in the contract,â says Bamforth. âWe have to make sure that these drugs are available in all countries of the world, not just in the first world who can afford them. “