25 Aug 2020

Why scientists are looking at existing medications to treat Covid-19

4:19 pm on 25 August 2020

Scientists are looking for drugs already approved for use to treat coronavirus, but some that initially showed promise have shown no benefit upon further investigation.

Doctors with protective glasses, protective suits and masks before applying a treatment for a coronavirus patient at Istanbul University Medical Faculty Hospital in Istanbul, Turkey

Doctors with protective glasses, protective suits and masks before applying a treatment for a coronavirus patient at Istanbul University Medical Faculty Hospital in Istanbul, Turkey Photo: AFP

Aspirin was originally developed as a painkiller, but now many people take it every day to prevent heart disease.

Scientists are taking a similar approach in their hunt to find medications to treat coronavirus: looking for drugs already approved for use in managing certain conditions that show promise in treating Covid-19.

Using a repurposed drug is the easiest path to take when looking for a new medical treatment, explains infectious diseases expert Sharon Lewin, director of the Peter Doherty Institute for Infection and Immunity in Melbourne.

"We have a good understanding of its safety, and the safety evaluation of new drugs takes a long time," said Professor Lewin, who is the lead author on the Australian Rapid Research Information Forum's report on the most promising therapeutics for Covid-19.

That means for a repurposed drug, if you already have data on safety, you can skip phases of the clinical trials process. So instead of having to do phase I clinical trials you can go straight to either phase II, or in some cases phase III or a hybrid phase II and III.

That does not mean existing drugs that show some promise can get the green light straight away, however.

We asked Lewin and two other health experts what issues need to be considered when we're evaluating a repurposed treatment for Covid-19.

What we don't know about treating Covid-19

Given the newness of Covid-19 as a human disease, we still face dilemmas in how we should be treating it.

"We want a drug that reduces mortality and reduces time in hospital, or reduces the chance of going onto a ventilator," Lewin said.

We do not necessarily know that if we reduce the amount of virus in the nose or the lungs, people will get a clinical benefit, she said, or if you stop the virus from dividing when people have really mild disease, whether that will stop them cascading into severe disease.

Famous repurposed drugs like antimalarial hydroxychloroquine and HIV drugs lopinavir/ritonavir have shown no benefit in phase III randomised studies, Lewin said.

"That doesn't mean those studies shouldn't be done ... it says that those studies really should be done early, get an answer and move on."

Lewin is also sceptical of the chances that another headline-grabbing repurposed drug, headlice treatment ivermectin, will work.

"[It] doesn't have a favourable pharmacokinetic profile, meaning that in a test tube model you need very high doses to see an effect," she said.

"Those doses can't be achieved in people, at least in the current formulation."

Part of ivermectin's popularity is because it is easy to use, Lewin said, but she thinks we're past that point now in the pandemic.

"There are 150 studies done looking at ivermectin and people are saying 'why not?' ... but I actually think it's a waste of time doing that sort of thing because all clinical trials cost money, all of them require participation of people ... so just because it's easy doesn't mean it should be tested."

Timing is everything

Another aspect of treating Covid-19 that we're still learning about is which drugs to use when.

This is different to how we deal with other viruses.

"All of our strategies for dealing with HIV are targeted to the virus," Lewin said. "If you treat the virus, no matter if you're super sick or if you're mildly unwell, you get excellent clinical outcomes."

But that's not the case with Covid-19.

"It seems that most of the virus is replicating early in infection," she said.

"And most of the disease caused late in infection is from a dysfunctional immune response, which must be triggered by the virus."

A pharmacy tech pours out pills of Hydroxychloroquine at Rock Canyon Pharmacy in Provo, Utah, on May 20, 2020.

Hydroxychloroquine showed no benefit in phase III randomised studies Photo: AFP

So early in the disease we might use drugs that target the virus, but later the interventions need to shift to targeting the immune response.

We're seeing this in what the research is telling us about some of the more successful repurposed drugs for Covid-19, antiviral remdesivir and corticosteroid dexamethasone.

Remdesivir is better used earlier in the disease, and dexamethasone has a bigger impact late in the disease, Lewin said.

Currently, remdesivir is the only prescription medicine provisionally approved by the Therapeutic Goods Administration to treat Covid-19, says a TGA spokesperson.

Other medicines can be prescribed for Covid-19, but this is known as 'off-label use' as they're being prescribed outside their approved uses.

While this approach is legal, it does rely on the clinical judgement of the prescriber, who must take into account the potential risks and benefits of the treatment for their patient, and it's recommended they also inform the patient.

The potential for harm

It is well worth remembering that no drug is without side effects, says Nial Wheate, program director of undergraduate pharmacy at the University of Sydney.

"Every drug has some sort of adverse event associated with it," Wheate said.

"So the more medications you give people, the more you put them at risk."

Sometimes you may also need to reformulate a drug when you're looking to use it to treat a different condition.

For example, multiple sclerosis drug interferon-beta has shown promise in a recent clinical trial for Covid-19, but instead of it being injected as it is for MS, it's given via a nebuliser, which allows Covid-19 patients to breathe it in as a fine mist.

"In that case, it kind of did need to be reformulated because of what they're trying to do is get the drug into the lungs specifically," Wheate said.

Reformulation doesn't change how the drug works, he said, but it changes where in the body the drug goes, and how much of it you need for it to be effective.

For example, if you take a medication in tablet form only about 10 percent of the drug may be absorbed into your bloodstream. But the same medication given as an injection will see 100 percent of the drug get into your bloodstream so we can lower the dose accordingly.

When you reformulate a drug you have to go back to phase I clinical trials to gather safety data on that formulation, including any side effects of the dose and where it's going in the body.

Wasting our opportunity to learn

Paul Glasziou understands why people are asking "What's the harm?" when it comes to using existing medications to treat Covid-19. But he has many concerns regarding the approach.

"I think that the biggest worry is that the drugs may actually prove to be harmful," Glasziou, director of the Institute for Evidence-Based Healthcare at Bond University, said.

But his second concern is that by haphazardly prescribing different treatments for Covid-19 and not studying them properly, very few people will be given the most effective treatments and we won't learn anything.

"Interestingly, people's guesses in this pandemic have been clearly wrong," Glasziou said.

For example, initially some people complained that it was unethical to test dexamethasone, he said, because the immune suppression effects of the drug were thought to be dangerous to patients.

However it became the first drug shown to reduce mortality rates among Covid-19 patients.

Glasziou said we're not very good at telling what will really work in practice.

He points to the RECOVERY Trial at the University of Oxford and the WHO's international Solidarity Trial, as examples of the definitive research we need to be doing to know what works and what doesn't.

"If we guess our way through the epidemic, we're going to learn nothing and the treatments won't be effective."


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