No pharmaceutical products have yet been shown to be safe and effective for the treatment of COVID-19. However, a number of medicines have been suggested as potential investigational therapies, many of which are now being or will soon be studied in clinical trials.
The coronavirus disease 2019 (COVID-19) drug pipeline is not growing at quite the same speed as the pandemic. But its rate of expansion is nevertheless cause for pause. In the months since COVID-19 has spread, researchers have launched more than 180 clinical trials of everything from repurposed antivirals and immunomodulators to unproven cell therapies and vitamin C. There are good reasons to build up a full pipeline of COVID-19 drugs. Up to 90% of new entrants into clinical trials never make it to approval, and so investigators want to have as many shots on goal as possible. Scientific understanding of COVID-19 is also changing so quickly that it makes sense to keep options open.
And in the absence of comprehensive trial coordination mechanisms, signs of disarray are emerging. The scale of these trials is too small, and the variation in terms of how they are being run is too large. These trials aren’t really designed to answer the questions that need to be answered. The research community faces a tricky dilemma, with little time for reflection. On the one hand, we want to be coordinated. On the other hand, we don’t want to spend too much time getting coordinated because the pace of this thing is so rapid. Everyone’s doing their best.
Efforts of countries with WHO
In the context, the World Health Organisation (WHO)) has now taken steps to provide greater coordination through its Solidarity trial, a study of four therapeutic approaches for hospitalised patients with confirmed COVID-19. These consist of Gilead’s RNA polymerase inhibitor remdesivir, the antimalarials hydroxychloroquine and chloroquine, the HIV protease inhibitors lopinavir and ritonavir, and lopinavir and ritonavir in combination with the immunomodulatory agent interferon beta-1a. First results could be available within 12–16 weeks. This trial seeks to align the research community behind key clinical trial design features that can make the most of incoming data.
By enrolling patients from around the world, the Solidarity trial might be able to answer questions more quickly than standalone trials can. Already, 70 countries have committed to joining up. Countries with the least developed health-care infrastructures can follow a backbone protocol, whereas those with better capabilities will launch “daughter” trials that will collect additional data.
As one expert says although the trial is not double-blinded, that is acceptable in a pandemic because we really want to make this as easy and simple as possible. By enrolling as many and as diverse a population as possible, the data will be more likely to reflect real-world efficacy. The chairman of the group of was quite hopeful about its outcome and said that although I am not saying these will be a cure for COVID-19 but adds. “But even if we can reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems.”
Other pipeline trial and testing
This leaves plenty of room—and need—for other agents. Beyond the traditional antivirals, a few candidates are already attracting attention. Virally targeted antibodies might be able to help the immune system to ward of infection, for example. There is also hope that anti-inflammatory agents might be able to keep overactive immune responses in check.The different classes of agents might also be most useful in different stages of diseases.
Antiviral agents, for example, might be most beneficial when used as early as possible in the course of disease, prophylactically even if possible. Anti-inflammatory agents might, by contrast, be harmful if used early on, if they dampen the immune response too much. Many more trials, consequently, are going to be needed. WHO might yet start another Solidarity trial in an earlier disease setting. Other large trials to build up the evidence base include the UK’s multiarm RECOVERY trial in hospitalised patients, which has already recruited 4 300 patients and is adding 400 more a day, and an international 40 000-patient prevention trial with chloroquine and hydroxychloroquine.
Industry sponsored trials will also be needed, both to prioritise which agents to test at scale and potentially to secure regulatory approvals. Gilead is aiming to recruit more than 3000 patients into its phase 3 trial of remdesivir, in addition to its collaborative efforts with WHO, the US National Institutes of Health, and others.
Searching for lasting medicinal effects
While finding effective drugs is no easy feat on its own, it is also only at best a single step on a long journey towards taming the COVID-19 beast. Manufacturing, regulatory approval, and supply and access decisions are also going to need collective solutions, as will vaccine and diagnostic development. It remains to be seen how this will all play out, but we are all working through different options and trying to help each other out. SARS-CoV-2 the coronavirus that causes the disease COVID-19 is completely new and attacks cells in a novel way.
Every virus is different and so are the drugs used to treat them. That’s why there wasn’t a drug ready to tackle the new coronavirus that only emerged a few months ago. The new coronavirus isn’t giving the world that kind of time. With most of the world on lockdown and the looming threat of millions of deaths, researchers need to find an effective drug much faster. This situation has presented before us the challenge and opportunity of a lifetime: to help solve this huge public health and economic crisis posed by the global pandemic of SARS-CoV-2.
The pathways into a human cell are normally locked to outside invaders, but the coronavirus uses its own proteins like keys to open these locks and enter a person’s cells. Once inside, the virus binds to proteins the cell normally uses for its own functions, essentially hijacking the cell and turning it into a coronavirus factory. As the resources and mechanics of infected cells get retooled to produce thousands and thousands of viruses, the cells start dying. Lung cells are particularly vulnerable to this because they express high amounts of the “lock” protein SARS-CoV-2 uses for entry. A large number of a person’s lung cells dying causes the respiratory symptoms associated with COVID-19.
There are two ways to fight back. First, drugs could attack the virus’s own proteins, preventing them from doing jobs like entering the cell or copying their genetic material once they are inside. This is how remdesivir a drug currently in clinical trials for COVID-19 works. A problem with this approach is that viruses mutate and change over time. In the future, the coronavirus could evolve in ways that render a drug like remdesivir useless. This arms race between drugs and viruses is why we need a new flu shot every year. Alternatively, a drug can work by blocking a viral protein from interacting with a human protein it needs. This approach essentially protecting the host machinery has a big advantage over disabling the virus itself, because the human cell doesn’t change as fast. Once we find a good drug, it should keep working and it may also work against other emergent viruses.