Draft results accidentally published Thursday by the World Health Organization (WHO) on its website showed that Gilead Sciences’ closely watched COVID-19 candidate remdesivir failed to show clinical improvement in severely infected patients in a Chinese Phase III trial.
According to the draft, whose findings were disclosed by The Financial Times, remdesivir had not reduced the presence of SARS-CoV-2 in the bloodstream of 158 patients treated with the antiviral candidate in the 237-patient trial (NCT04257656). Eighteen patients were taken off the drug due to side effects.
“Remdesivir use was not associated with a difference in time to clinical improvement,” or mortality after 28 days, or in time to SARS-CoV-2 PCR, the draft stated, according to several published reports.
Twenty-eight days after treatment, 13.9% of the patients in the remdesivir cohort died, compared to 12.8% of untreated control patients—a difference the researchers concluded was not statistically significant.
“In this study of hospitalized adult patients with severe COVID-19 that was terminated prematurely, remdesivir was not associated with clinical or virological benefits,” according to the draft.
Gilead stopped short of calling the trial a failure in a statement that acknowledged that the study was halted early. The drug developer said it believed the draft contained “inappropriate characterizations of the study,” and added that the trial’s investigators did not give permission for publication of their results.
“The study was terminated early due to low enrollment and, as a result, it was underpowered to enable statistically meaningful conclusions,” Gilead stated. “As such, the study results are inconclusive, though trends in the data suggest a potential benefit for remdesivir, particularly among patients treated early in disease.”
Data from the study has been submitted for peer-reviewed publication, “which will provide more detailed information from this study in the near future,” Gilead added.
In a separate statement, the WHO said the draft document “was inadvertently posted on the website and taken down as soon as the mistake was noticed.”
“Surprising and disappointing”
“These results are surprising and disappointing in light of recent positive ‘anecdotal’ commentary from a U.S. study investigator suggesting that remdesivir was associated with rapid improvements in clinical status in severe subjects enrolled in the Gilead sponsored U.S. study,” SVB Leerink director of therapeutics research and senior research analyst, Geoffrey C. Porges, wrote in an investor note along with colleagues Neil Puri, MD, Ke (Andrew) Yuan, and Bradley Canino..
On April 16, leaked preliminary results first reported in STAT showed that remdesivir treatment in severe COVID-19 patients in another Phase III trial (NCT04292899) led to rapid recoveries in fever and respiratory symptoms with nearly all patients discharged in less than a week. The publication obtained a video discussion of the findings by the investigator conducting the trial at the University of Chicago, one of 169 treatment sites. Gilead responded with a statement emphasizing: “The totality of the data needs to be analyzed in order to draw any conclusions from the trial,” while UChicago Medicine stated: “Drawing any conclusions at this point is premature and scientifically unsound.”
While acknowledging that the data from the terminated Chinese trial was not definitive, Porges and his SVB Leerink colleagues added: “It does suggest that the treatment effect in severe patients is likely to be small, even if future data updates from U.S. studies are positive.”
“Overall, we are less optimistic that remdesivir will be able to demonstrate substantial clinical benefit in severe patients,” Porges and colleagues added. “However, we remain cautiously optimistic that remdesivir could still show meaningful efficacy if administered earlier, and in less severe patients, prior to the onset of immune-mediated tissue damage and end-organ dysfunction (particularly within the lungs).”
Second trial ends early
The Chinese trial in severe COVID-19 patients was the second Phase III study of remdesivir in China to end early due to low enrollment; the trial was originally supposed to enroll 453 patients. The inability to enroll patients was a consequence of the decrease in COVID-19 cases since the winter, the trial sponsor, China’s Capital Medical University, stated on the study’s page on ClincalTrials.gov: “The epidemic of COVID-19 has been controlled well in China, no eligible patients can be enrolled at present.”
On April 15, Capital Medical University also disclosed on ClincalTrials.gov that enrollment was suspended in a Chinese trial designed to assess remdesivir in patients with mild-to-moderate forms of COVID-19 (NCT04252664). That trial was a randomized, double-blind, placebo-controlled multicenter study intended to evaluate remdesivir’s safety and efficacy in hospitalized adults. The trial’s estimated enrollment was 308 patients.
That same day, Gilead trumpeted a cohort analysis of 53 patients hospitalized with severe complications of COVID-19 who were treated with remdesivir on an individual compassionate use basis.
According to the cohort analysis, published in The New England Journal of Medicine, treatment with remdesivir resulted in an improvement in oxygen support class for 36 of the 53 patients (68%) over a median follow-up of 18 days from the first dose. Seventeen of 30 patients on a ventilator were extubated (57%), while 25 of the 53 patients (47%) were discharged from the hospital following treatment with remdesivir.
After 28 days of follow-up, the cumulative incidence of clinical improvement—defined as discharge from the hospital and/or at least a two-point improvement from baseline on a predefined six-point scale—was 84%, according to Kaplan-Meier analysis. Clinical improvement was less frequent among patients on invasive ventilation versus noninvasive ventilation, and among patients at least 70 years of age, Gilead said.
However, Gilead acknowledged that compassionate use data was limited in utility due to the small size of the cohort, the relatively short duration of follow-up, potential missing data due to the nature of the program, the lack of information on eight patients initially treated, and lack of a randomized control group.