Re-purposing familiar drugs to defend against COVID 19

The name Thalidomide still sends a shudder through the world of pharmaceutical and medical world. Used in the 1960s to treat severe morning sickness, it was found to cause harrowing birth defects. It’s believed more than 10,000 babies in 46 countries were affected. The problem was later discovered to be related to its chirality. One of its stereoisomers (the S-enantiomer) caused foetal genetic damage.

In today’s world, Thalidomide has been rehabilitated. We use it under the name Immunoprin helping suppress the immune system to reinforce cancer treatments for multiple myseloma.

The licensed anti-depressant trazodone hydrochloride and an anti-cancer compound dibenzoylmethane (DBN) have both been shown to reduce the brain shrinkage attributed to Alzheimer’s and associated neuro-generative diseases. Together they also appear to block a pathway linked to brain cell death caused by prion disorders like Creutzfelt-Jacob disease.

There is promising circumstantial evidence that aspirin (acetylsalicylic acid) might be useful in cases of lupus.

These are all good examples of drugs used in one medical context turning a new trick. The problem is identifying those applications and once they are discovered getting them approved and licensed for the new role.

The clock is against us

In the teeth of this pandemic, the clock is against everybody and any drug which shows promise, deserves our attention. But finding compounds that could be a useful therapy against coronaviruses is painstaking. Imagine sending a darts player blindfold into a darkened room and asking him to hit the bullseye. That’s the scale of the task facing researchers.

Recently in California a team at Sanford Burnham Prebys Medical Discovery Institute, led by Dr Sumit Chanda California launched a massive assault on COVID 19 cells in vitro using 13,000 separate compounds. They are hoping to filter out those that slow the virus growth. 

The team has already isolated some 'candidates' by reducing their doses to mimic the levels that that would function in a typical patient’s lungs. 

Last month (April 17) the initial report was published. It has yet to be peer-reviewed but six drugs showed particular promise. One is already used to treat osteoporosis and another which has shown promise as a treatment for arthritis.

Dr Chanda has been honest about this blunderbuss method, telling one reporter he knew 96 to 98 per cent of the compounds were going to fail. “However, we only need one or two to show promise for a potential breakthrough,” he said.

In 2012, the MERS coronavirus emerged in the Middle East, and Dr Matthew Frieman, a virologist at the University of Maryland School of Medicine responded by setting up a drug-repurposing study. He put a mere 290 US FDA approved drugs to the test and found that 27 of them blocked the MERS virus from infecting cells. 

These have also proved effective against the related coronavirus that causes SARS.

Dr Frieman and his colleagues have now tested those drugs against the COVID-19, It’s early days but a preliminary report flags optimism over 17 of them.

Along with chlorpromazine, favoured against malaria, they include drugs for disorders as varied as Parkinson’s disease and leukaemia. Similar work is being carried out in research labs in most countries which have hi-tech resources. Some are starting tests on animals. 

Meanwhile Dr Frieman is as honest as Dr Chanda: “We just don’t know a lot about why drugs do what they do.” 

What price the future of R&D after COVID 19? 

A report in 2014 concluded that the cost of developing new drugs through the complex processes of initial research, to trials and eventual marketing, is $2.6bn (£2bn). Since then these costs have increased by an estimated 145%. 

Patent protection for new drugs in general lasts over twenty years but the US FDA will not allow the manufacturers to sell a new drug until it has approved and validated clinical trials. These trials take years, often as much as ten years, cutting into that crucial patent protection period.

Then there’s risk that a patented drug may have unexpected side effects further down the track. It’s been such a problem that it raises concern a day might come when there is no profit in new drugs and no incentive to do R&D.

Once we are on top of the pandemic, either with a vaccine or therapeutics or a combination of both, the world of pharmaceutical R&D will see some significant changes. It maybe that repurposing and virtual computer-aided drug design move higher up the methodological pecking order. 

Is the answer in the data?

The US-based charity Cures Within Reach has been advocating drug repurposing since 2011. A spokesman said it has always been a Cinderella in terms of research: “There are thousands of ideas inspired by underlying laboratory or animal data or clinical observations that point to other disease targets for drugs which are part of the regular scene.”

Looking for new uses for established drugs is more than just a case of outside-the-box thinking. Simple economics make it a sound option and mining existing data stores on these drugs could offer clues to new applications including potential COVID-19 therapies. 

Finding drug therapies to tackle extremely rare diseases has always had hidden benefits. Yet these ‘orphan diseases’ as they are known, do not provide much incentive for Big Pharma to explore their efficacy because any successful drug or derivative is likely to have only limited market value.

Re-purposing of a drug, if successful as a therapy, could bring a raft of fresh problems too. If a drug proves some a level of capability, supplies will inevitably be inadequate. Manufacturing might be difficult to upscale and distribution will problematic.

The WHO has had discussions with the bigger companies on how they would be able to produce drugs in large enough quantities. For example, generic drug makers have given assurances they could scale up to millions of doses of ritonavir and lopinavir, while still supplying the HIV-positive patients, who rely on the drugs.

Gilead in California, has enough remdesivir, to support clinical trials and compassionate use. The company says it is working to make more available “as rapidly as possible”, even in the absence of conclusive evidence that it works and works safely.

The mechanisms by which COVID-19 invades human cells will eventually by understood and we will unlock the door to safe vaccines. Until we do, we must employ all tactics in to mitigate against it and the answers to some of the questions may lie on the experience and data we already have on existing drugs.

References

https://www.biorxiv.org/content/10.1101/2020.04.16.044016v1
https://clinicaltrials.gov/ct2/show/NCT04366739
https://www.frontiersin.org/research-topics/6471/virtual-drug-design