Do existing drugs work against COVID?

So far,most drugs repurposed from the medicine cabinet have failed against COVID – from Donald Trump’s pick,hydroxychloroquine,to the anti-HIV combination lopinavir/ritonavir. The commonantiparasitic drug ivermectin is still being trialed,Tong says. “But in[severe] cases,we now know hydroxychloroquine can even make things worse”. Doctors around the world have often faced a harrowing choice between waiting for treatment trials to finish and offering experimental therapies to the dying patients before them in the meantime.

Two drugs work well enough that they are now standard in COVID hospital wards,including in Australia:the antiviral remdesivir,formulated to fight Ebola and somewhat effective in stopping the coronavirus replicating in cells,and the inexpensive steroid dexamethasone,which dampens that dangerous immune system overreaction. Dexamethasone is the stand-out,shown to bring down the risk of death by a third for COVID patients on ventilators,and nearly a fifth for those on oxygen therapy (“There’s no silver bullet but we’re very confident that saves lives,” Tong says).

Remdesivir has hadmore disappointing results in terms of reducing mortality,Tong says,but is still considered safe. “Patients will often get both together in hospitals. There’s also another anti-inflammatorytocilizumab that’s directed against a specific cytokine I’ve used for[patients] and that’s been shown to work too.”

Can we just give people the antibodies they need?

Vaccines tell your immune system which antibodies to make to fight off COVID-19;they then gum up the signature spike protein the virus uses to break into cells. But,for someone already infected,or someone with a compromised immune system,doctors can put antibodies directly into the body via transfusion. Before vaccines arrived,this was already being tried by “borrowing” the immunity (antibodies) still active in the blood plasma of recovered COVID patients. But,despite urgent calls for survivors to donate their plasma and a large rollout in hospitals worldwide,Tong says it has since beenfound not to help patients as first hoped. ASCOT halted its own test of plasma transfusions in February of this year.

Instead,designer antibodies engineered in the lab,known as monoclonals,are proving very effective at stopping patients early on from developing severe disease. “They’re engineered to go after the spike just like the vaccine,” Tong says. The treatment is already approved in the United States and Tong says it would be good tosee it come to Australia,too. “When people test positive who we know are at higher risk of severe disease,those who have[underlying conditions] like diabetes or are older,then we could give it to them proactively.”

Kelleher says that,as with most of the existing drugs tested on COVID,monoclonals have a long safety record,often cooked up for cancers,hepatitis and autoimmune conditions. They work especially well in patients whose immune system does not kick in strongly against COVID.

“Eventually,we might be testing a patient’s initial antibody response and then coming up with the best treatment algorithm from there,” Kelleher says. Kirby Institute researchers are part of a global trial testing newly developed monoclonals in places such as Indonesia and South America,with plans to trial designer anti-viral drugs next.

But monoclonals are also expensive and difficult to make,Kelleher says.They are given intravenously at present,posing a challenge for delivery to early-stage patients outside a hospital. And some already appear vulnerable to evolving variants of the virus.

Although there is some evidence emerging that the more contagious Delta variant also has a higher hospitalisation rate,Tong says it’s not clear yet and overall “we don’t know if the response to treatment varies by variant”. Certainly,therapies focused on dampening the body’s immune response won’t be. And as Kelleher adds:“Not all drugs are aimed at the spike protein,that’s the bit[of the virus that keeps mutating],so they might not be as vulnerable as monoclonals.”

Could we take a pill to stop a bad case of COVID?

That’s the hope. So far a number of candidates have failed. But Pfizer,one of the makers of mRNA vaccines for COVID,is in the late stages of testing an antiviral pill to stop more severe disease developing,which it hopes to have available by the end of the year. The US government has already agreed to pay Merck&Co. $US1.2 billion ($1.6 billion) for the company’s own experimental antiviral molnupiravir if it clears regulators. Preventative nasal sprays that kill the virus as it enters the body via the nose and mouth are also being tested. There’s even work underway by Australian and US scientists onnanoparticles that can be delivered directly to the lungs like “heat-seeking missiles” to stop an infection taking hold there. Meanwhile,the inhaledsteroidal asthma medication budesonide has been shown to reduce the chance of more severe disease if taken early.

Outside the frenzied focus of a pandemic,new drugs face a similarly slow path to development as vaccines do. But Kelleher notes respiratory viruses are notoriously difficult to make anti-virals and other treatments for,trickier than,say,making antibiotics to fight bacteria. “Even[the influenza antiviral] Tamiflu only reduces the severity of the flu by a couple of days.”Robots have been screening millions of chemical compounds since early 2020 to find the best COVID-fighting potential,but that’s just in labs. “And when you do find something,most will fail in people or have[bad side effects],” Kelleher says.

Tong says treatment development for COVID would benefit from more focus and funding. “We needa pipeline to get therapies into clinical trials earlier and in a more co-ordinated way.” He points to the example of the failed plasma trials. “In the US,in particular,hundreds of thousands of people have had it,often on compassionate grounds[not just in trials] and with great expense,and now the evidence says it doesn’t seem to work. If those trials had been bigger earlier,we might have known sooner.”

Kelleher agrees that the world’s focus on vaccine development is crucial,but treatments for COVID are urgently needed,too. “For those people where the virus has got around the vaccine or their bodies haven’t generated the antibodies as we’d hoped,this is where you save them.”

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