ViewPoints: Initial glimmers of hope for COVID-19 therapeutics

After weeks of speculation based largely on anecdotal evidence, data from two human trials were published this week and the results were reportedly chequered, but leave plenty of room for optimism.

The backstory

The biopharma industry is in the midst of a mad scramble to identify and test therapeutics in the hopes of bending the curve of the ongoing COVID-19 pandemic. At least a dozen candidates have already been moved into human testing less than three months after the first cases of infected patients were described, which in a different time and place might be cause for self-congratulation.  

As it stands, though, the only thing that matters is that something proves successful in lightening the load on healthcare systems around the world that in certain instances are functioning well beyond maximum capacity.

What happened

On March 19, the world got its first look at not one, but two clinical studies evaluating the safety and efficacy of possible COVID-19 therapeutics. Both trials had been launched in China in the immediate aftermath of the initial outbreak.

One appearing in the New England Journal of Medicine evaluating Kaletra (lopinavir/ritonavir) was described as a top-line failure as researchers observed no benefit in severely ill patients hospitalised with COVID-19 when the HIV drug was added to standard of care (SOC).

The other trial compared Fujifilm Toyama Chemical's Avigan (favipiravir) to Kaletra and found that the former drug substantially shortened the time to viral clearance (roughly 4 days versus 11 days, respectively). In addition, 91% of patients on Avigan experienced improvement on chest computed tomography scans compared to 62%.

What matters most

Headlines for the two studies indicated the findings were clearly negative for Kaletra in the first and definitively positive for Avigan in the second. However, there are reasons for exercising caution on both accounts beyond the most obvious caveat that neither of the studies was randomised.

The overall analysis in the "failed" Kaletra trial did indeed show that the drug had not achieved a benefit when added to SOC on the all-important measure of mortality. Specifically, the 28-day mortality rate for the treatment arm was 17%, which surpassed the 25% in the control group, but did hit the threshold for significance.

Nevertheless, Evercore ISI analyst Umer Raffat remarked that it would be more relevant to take into account when an antiviral agent is given relative to when the symptoms emerged in order to determine its efficacy. This concept has been validated by the likes of Roche's influenza drug Tamiflu (oseltamivir), he noted.

In fact, a much stronger trend emerges when the data set is parsed for patients who received therapy within 12 days of symptom onset, with 28-day mortality rates of 15% for Kaletra and 27% for SOC. Raffat believes that digging deeper and comparing patients who had symptom onset within eight days would only strengthen the drug's potential efficacy profile.

On the flipside, while Avigan's performance looked encouraging, it must be taken with a pinch of salt given the non-randomised nature of the study, which could potentially have been confounded by the fact that patients recruited between January 24 and January 30 were all placed in the Kaletra arm while all of those enrolled after received Avigan.

Raffat acknowledged that patients in the Avigan cohort all began treatment later, at which point physicians would have had more experience in managing the outbreak, is an important shortcoming of the study.

What next?

One of the more hotly anticipated readouts looming on the horizon is from a Phase III trial being conducted in China in which Gilead Sciences' remdesivir is being tested in 453 severely ill patients with COVID-19.

Raffat noted that this study bears a lot of resemblance to that of Kaletra that reported out this week. A feature that should play to remdesivir's advantage is that the Gilead candidate's antiviral activity against COVID-19 in vitro is significantly more potent than the HIV drug.

On the other hand, the trial of favipiravir offered a number of advantages that may portray that agent in a better light, perhaps most notably the fact that patients were only enrolled if the onset of symptoms had begun within one week. The remdesivir study accepted patients up to 12 days after their symptoms had emerged.

As such, Raffat warned that focusing on the overall analysis from the remdesivir study may not be the most appropriate way of looking at the results. "Instead, all that matters is this: how many days post symptom onset does remdesivir remain active? That subgroup is all that matters," he stressed.

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