First drug repurposing trial for COVID-19 falls flat

Posted: March 19, 2020 in Uncategorized
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By Anette Breindl

The first attempt at using existing drugs to treat patients infected with SARS-CoV-2 has yielded disappointing results.

In 200 hospitalized patients with severe COVID-19, a 14-day regimen of twice-daily treatment with Kaletra/Aluvia (lopinavir/ritonavir, Abbvie Inc.) did not hasten recovery when added to the standard of care. Chinese clinicians led by Bin Cao of the National Clinical Research Center for Respiratory Diseases reported their findings in the March 19, 2020, issue of The New England Journal of Medicine.

Lopinavir is a protease inhibitor, while ritonavir increases the half-life of lopinavir by inhibiting its metabolism. The drug was tested because screening studies had flagged it as having activity against MERS-CoV, which has led to a clinical trial of a combination of Kaletra/Aluvia and interferon-beta for the treatment of MERS-CoV in the Kingdom of Saudi Arabia.

In the COVID-19 trial, 199 patients were treated, split evenly between drug and standard-of-care groups. The study’s primary endpoint, time to improvement, was the same between the two groups, both of which took 16 days to improve. Mortality and viral load at various time points were also not different.

In an editorial published alongside the paper, Lindsey Baden, of Harvard Medical School, and Eric Rubin, of the Harvard TH Chan School of Public Health, wrote that “the results for certain secondary endpoints are intriguing,” but also acknowledged that those results were hard to interpret, due to a mix of trial size, possible differences in illness severity at baseline, and the fact that the trial was randomized but not blinded.

And if certain endpoints were intriguing, others were discouraging. In particular, viral loads did not differ between the groups, tellingly so, according to Baden and Rubin. “Since the drug is supposed to act as a direct inhibitor of viral replication, the inability to suppress the viral load and the persistent detection of viral nucleic acid strongly suggest that it did not have the activity desired,” they wrote. “Thus, although some effect of the drug is possible, it was not easily observed.”

It is possible that larger trials will yet uncover an effect of Kaletra/Aluvia. But for now, perhaps the best hope is that other drugs will work better – in particular, remdesivir (Gilead Sciences Inc.), which was originally developed for Ebola virus disease, but proved less effective there than several other options.

A paper in the Jan. 10, 2020, issue of Nature Communications investigated the effects of Aluvia on MERS-CoV in mouse experiments, where it showed ho-hum effects. The authors of the Nature Communications paper reported that “prophylactic [Kaletra/Aluvia plus interferon-beta] slightly reduces viral loads without impacting other disease parameters.”

But remdesivir was more effective. “Both prophylactic and therapeutic [remdesivir] improve pulmonary function and reduce lung viral loads and severe lung pathology” in a mouse model of MERS, the authors reported.

Remdesivir is in both an NIH-sponsored clinical trial and a Japanese-Chinese trial as potential COVID-19 treatment, after a January case report of a patient who showed rapid improvement after he was treated with the drug for COVID-19.

Though the Kaletra/Aluvia trial’s results were not as hoped, Baden and Rubin noted that the trial itself was an encouraging bit of news, as well as a “heroic effort…. As we saw during the 2014 Ebola outbreak in West Africa, obtaining high-quality clinical trial data to guide the care of patients is extremely difficult in the face of an epidemic, and the feasibility of a randomized design has been called into question. Yet Cao’s group of determined investigators not only succeeded but ended up enrolling a larger number of patients (199) than originally targeted.”

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