Without an approved drug to tackle the novel coronavirus, scientists and biopharma companies are busy looking to repurpose existing therapies. One of the earliest efforts in that direction seems to have hit a snag—but at least one analyst refuses to call it a dead end.
AbbVie’s HIV med Kaletra (Aluvia), a combination of antiviral drugs lopinavir and ritonavir, failed across the board in a 199-patient clinical trial. It didn’t top standard of care at improving clinical symptoms, extending lifespan or cutting viral shedding in patients hospitalized with severe COVID-19, results from a study published Wednesday in The New England Journal of Medicine show.
Physicians at China’s Jin Yin-tan Hospital in the city of Wuhan—which was until recently the epicenter of the outbreak—therefore concluded that Kaletra doesn’t offer additional benefits over standard care in COVID-19. But Evercore ISI analyst Umer Raffat begs to disagree.
Basically, the team shouldn’t look at overall results from the study, Raffat argued in a Wednesday note to clients.
Because it was one of the earliest clinical trials of COVID-19—the first patients enrolled on Jan. 18, just a week after SARS-CoV-2 had been identified and sequenced—little was known about the virus. And the patients had already been showing symptoms for about two weeks when they entered the study.
That’s “very long,” Raffat said, noting that Roche’s flu drug Tamiflu needs to be initiated less than two days from symptom onset.
Because nobody knows when a patient's SARS-CoV-2 viral load peaks, the study should have focused on “identifying the time point up until which an antiviral may work,” he said.
In fact, if we zero in on patients that received Kaletra earlier, a clearer mortality benefit shows up. According to the study, the death rate in Kaletra patients was 15.0% at day 28, versus 27.1% among placebo patients, provided therapy started within 12 days of symptoms starting, Raffat noted. When all modified intention-to-treat patients are analyzed, the difference narrowed to 16.7% versus 25.0%.
“Honestly, I want to see a further sub-cut of this data … perhaps for patients that initiated [Kaletra] less than eight days from symptom onset,” Raffat said.
In a separate editorial that ran alongside the study, infectious disease specialists Lindsey Baden, director of clinical research at Brigham and Women’s Hospital; and NEJM Editor-in-Chief Eric Rubin also looked for silver linings.
Though they called the results “disappointing,” Baden and Rubin pointed to the fact that the team chose a challenging population to study, because the patients recruited were already late in the disease course and already had major tissue damage. “Even highly active antibacterial agents have limited efficacy in advanced bacterial pneumonia,” they wrote.
To put it into perspective, as of Thursday, China has reported 81,263 infections of the novel coronavirus, with 3,250 deaths. That translates into an overall mortality rate of 4%, far lower than the double-digit percentages seen in the Kaletra trial.
But perhaps the more worrisome data lies in Kaletra’s inability to cut viral load, which is important because the drug is meant to directly target the virus rather than merely relieving symptoms. At day 28, SARS-CoV-2 RNA was still detected in 40.7% of the patients on Kaletra.
Lopinavir and ritonavir inhibit protease, an enzyme HIV and coronaviruses use to replicate. The combo first attracted interest after a pulmonary and critical care physician dispatched to Wuhan said Kaletra had healed his disease. China’s National Health Commission soon added the med to its COVID-19 clinical guidance and has kept it there in all its subsequent updates.
Earlier this month, AbbVie said it’s collaborating with health authorities, including the U.S. FDA, to determine Kaletra's antiviral activity in COVID-19 patients, as well as efficacy and safety.
Other drugs recommended by the Chinese guidance include an influenza med called Arbidol (umifenovir) that’s not approved in Western countries, the standard malaria drug chloroquine, as well as old antiviral ribavirin and interferon-alpha, among others.
Chinese scientists and Gilead Sciences are also examining the latter’s antiviral drug remdesivir, which has so far shown the most promise against the novel coronavirus.
Bin Cao, the lead author of the Kaletra study, is also leading the Chinese clinical study on remdesivir—and that has Evercore ISI’s Raffat concerned that the overall remdesivir trial may be presented the same way.
“We should look specifically for patients that initiated remdesivir fast enough,” he argued. “[T]he entire purpose of [the] trial is to define that dosing window.”