Drug discovery and testing, even under normal circumstances, is a high-risk process full of red herrings and dashed hopes. In the throes of a global pandemic, the stakes are even higher and the risks remain the same. So although the news last week that the promising Covid-19 drug remdesivir seems to have failed a major trial was certainly disappointing, it was not surprising.
It usually takes about two decades to go from a promising lab “eureka” to a marketed drug. The dicey territory in between is known as “the valley of death” for good reason: the failure rate for a drug entering clinical trials has been estimated at more than 90%, and many startups go under before their therapy idea even makes it that far.
Now years are being compressed into weeks. Researchers are throwing everything they have at the virus, including various drugs that have already been approved for other uses, experimental drugs that didn’t work for other diseases but might just work for Covid-19 – and even banal substances like vitamin C. At the last count, there were more than 300 clinical trials ongoing or about to recruit worldwide. A lot of drug testing is also happening outside of formal trials under “compassionate use” regulations, which allow unapproved drugs to be used on seriously ill patients with no other recourse.
It’s important to note that these drugs are not vaccines, they are treatments. Vaccines prevent disease altogether, saving a huge amount of healthcare expenditure and heartache, but drugs like these play an important role in treating those who become ill. And even when we have a Covid-19 vaccine, protection is not likely to be 100%, so treatments will still be useful.
Remdesivir was initially developed as an Ebola therapy by the American company Gilead Sciences. It targets the specialised process of genome copying in viruses, which contain an RNA blueprint instead of its cousin DNA. Coronaviruses also have RNA genomes and in animal experiments, remdesivir showed activity against the related coronaviruses that cause Sars and Mers. Hopes were raised further when the drug performed well on primates infected with Sars-CoV2 and was associated with some improvement in a small compassionate use patient study published in the New England Journal of Medicine. But the gold standard is a randomised control trial, and an accidentally posted memo suggested that Gilead’s trial had been terminated early due to side-effects with no improvement seen over placebo.
It’s not necessarily the end for remdesivir. Gilead has since said that the early termination of its trial meant the results were inconclusive, not a failure, because recruitment numbers weren’t high enough to necessarily see a difference. A formal publication describing all the details has already been fast-tracked. In the meantime, there are five other trials of remdesivir ongoing, including a few gold-standard randomised trials. Reports on Wednesday suggested that the preliminary results in one of these, conducted by the National Institute of Allergy and Infectious Diseases, showed improved recovery times compared to placebo.
Although people prefer their science to be black and white, clinical reality is rarely that definitive. New therapies can fail one key trial and still go on to become a marketed drug. This is because different trials have different parameters: the patient population can vary, or they might employ different doses, endpoints or measures of success. Crucially for antiviral compounds, which might be expected to work better at earlier stages of the disease, a patient’s level of sickness at the time of treatment is also a key consideration.
But whether remdesivir works or not, there are still all those other possibilities on the horizon. The World Health Organization chose three other potential therapies in addition to remdesivir to back in its Solidarity trial, which is supporting patient studies all over the world. These are interferon beta-1a, a molecule that our immune system produces; lopinavir, an approved treatment for HIV; and chloroquine/hydroxychloroquine, malaria drugs which have caused controversy due to their side-effects (as well as for being touted by Donald Trump). It’s worth noting that lopinavir and the malaria drugs have also failed previous trials for Covid-19.
One dark horse is Pepcid (famotidine), a widely used over-the-counter heartburn remedy. This unlikely solution came into focus when it was noticed that some Covid-19 survivors had been on the medication – a testimony to how serendipity and close observations can play key roles in medicine – and trial results are expected in a couple of weeks.
Ultimately, the most effective way of controlling the pandemic is through immunisation. But with a vaccine months or even years away, and even then not totally assured, a viable therapy could make all the difference in the meantime. The world will be watching the results of these hundreds of trials closely, with fingers very much crossed.