WHO stands by COVID-19 study casting doubt on benefit of Gilead's Veklury

Interim findings from the World Health Organization's (WHO) global Solidarity trial have been posted to the medRxiv preprint server, and the agency says Gilead Sciences' Veklury (remdesivir) and the other drug regimens tested had "little or no effect" on 28-day mortality or the in-hospital course of COVID-19 among hospitalised patients. The data appear to corroborate a recent report based on a copy of the study that was obtained by the Financial Times.

"In just six months, the world's largest randomised control trial on COVID-19 therapeutics has generated conclusive evidence on the effectiveness of repurposed drugs for the treatment of COVID-19," the WHO stated.

The trial included 11,266 adult patients with COVID-19 across 405 hospitals in 30 countries. Study drugs were Veklury, hydroxychloroquine, a fixed-dose combination of lopinavir plus ritonavir, as well as interferon-beta1a, initially with lopinavir, and later not. According to the report uploaded to medRxiv, patients were randomised equally between whichever study drugs were locally available and open control. This could go up to five options, consisting of four active treatment arms and local standard-of-care. A total of 2750 inpatients were allocated Veklury, 954 hydroxychloroquine, 1411 lopinavir, 651 interferon plus lopinavir and 1412 only interferon, while 4088 received no study drug.

No significant decrease in deaths

The trial looked at the effects of these treatments on overall mortality, initiation of ventilation, and duration of hospital stay. There were 1253 deaths reported in the study, with 28-day mortality of 12%. Death rates were higher if patients were already ventilated at randomisation than if not, at 39% and 10%, respectively.

According to the medRxiv report, mortality rate ratios for each drug versus its control were 0.95 for Veklury, 1.19 for hydroxychloroquine, 1.00 for lopinavir and 1.16 for interferon. The authors said "no study drug definitely reduced mortality (in unventilated patients or any other subgroup), initiation of ventilation or hospitalisation duration." They added that the "mortality findings contain most of the randomised evidence on [Veklury] and interferon, and are consistent with meta-analyses of mortality in all major trials." The WHO said the results are under review for publication.

Gilead questions study design

However, Gilead issued a statement highlighting limitations in the study's design, which it said "prioritised broad access, resulting in significant heterogeneity in trial adoption, implementation, controls and patient populations, and consequently, it is unclear if any conclusive findings can be drawn from [these] results."

The company also pointed to data from the Phase III ACTT-1 trial, recently published in the NEJM, which involved more than 1000 hospitalised adult patients with mild/moderate-to-severe symptoms of COVID-19. Results there suggested that adding Veklury to standard care sped up recovery times by five days and reduced disease progression, compared with placebo and standard-of-care. ACTT-1 also showed "a trend toward reduced mortality" in Veklury-treated patients compared with placebo, while in a post-hoc analysis, the antiviral drug was found to reduce mortality by a statistically significant 70% at day 29 among patients who were on low-flow oxygen at baseline, Gilead said.

Nevertheless, Richard Peto, an independent statistician hired by the WHO to scrutinise the Solidarity findings, said that the UN agency's study has produced "a reliable result, don't let anybody tell you otherwise, because they'll try to. This is real-world evidence." He also suggested that the ACTT-1 study's perceived benefit in keeping patients alive could have been due to chance, adding "there isn't sufficient emphasis based on the need for large numbers [of study participants] if you want really reliable results."

WHO director-general Tedros Adhanom Ghebreyesus said the Solidarity trial would continue, noting the study "is still recruiting about 2000 patients every month and will assess other treatments, including monoclonal antibodies and new antivirals."

EU reviewing WHO study data

Veklury is available in multiple countries, and is currently authorised for emergency use in the US as a treatment for all hospitalised patients with suspected or laboratory-confirmed COVID-19, regardless of the severity of their disease. It is also conditionally approved in Europe to treat the disease in adult and adolescent patients with pneumonia requiring supplemental oxygen.

Meanwhile, the European Medicines Agency (EMA) said it would review the Solidarity trial data "to see if any changes are needed to the way these medicines are used." Earlier this month, the European Commission reached a deal with Gilead for the supply of up to 500,000 treatment courses of Veklury to the EU, where several countries were reporting shortages. However, Yannis Natsis, a representative of patients' organisations on the EMA board, said the Commission "needs to present the reasons behind the rush to conclude the latest contract with Gilead and move to review it in light of the Solidarity trial findings."  

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