By Sarah Tilyou

Enough evidence has trickled in to support the use of the investigational antiviral remdesivir in patients with COVID-19 that the FDA has issued an emergency use authorization (EUA) for the drug in that setting, but experts underscore that the data remain preliminary and need to be confirmed.

The EUA allows remdesivir—being developed by Gilead—to be distributed in the United States and administered by health care providers to treat hospitalized patients with suspected or laboratory-confirmed COVID-19 that is defined as severe based on low blood oxygen levels or the need for oxygen therapy or more intensive respiratory support (bit.ly/2Su349P).

The FDA issued the EUA two days after National Institute of Allergy and Infectious Diseases (NIAID) investigators released positive preliminary findings from a randomized, double-blind, placebo-controlled phase 3 trial of the drug. In the trial, hospitalized patients with advanced COVID-19 who received remdesivir recovered faster than similar patients who received placebo. 

The trial—called Adaptive COVID-19 Treatment Trial (ACTT)—began on Feb. 21 and includes 1,063 patients at 68 sites—47 in the United States and 21 in countries in Europe and Asia (bit.ly/3aRIyWR; ClinicalTrials.gov Identifier: NCT04280705). In the study, patients are treated with 200 mg of remdesivir on the first day of enrollment and 100 mg per day on up to nine subsequent days of hospitalization (maximum, 10 days), or placebo.

Preliminary Analysis Shows Benefit 
An independent data and safety monitoring board overseeing the trial conducted a preliminary data analysis that indicated remdesivir reduced time to recovery—the primary end point—better than placebo. Recovery was defined as being well enough for hospital discharge or returning to normal activity level.
Patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P<0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. The results also suggested a trend for a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (P=0.059).

More detailed results from the trial, which closed to new enrollments on April 19, will be available in a report scheduled for release by the end of May (bit.ly/2KpDL45).

The early placebo-controlled results support positive findings from an uncontrolled compassionate use trial of the drug reported in mid-April (bit.ly/2YqnxjI), but they contrast with findings from a placebo-controlled trial of 237 Chinese patients that showed “remdesivir was not associated with statistically significant clinical benefits” (Lancet 2020 Apr 29. doi: https://doi.org/10.1016/S0140-6736(20)31022-9).

Early NIAID Study Results ‘Encouraging’

Jeffrey R. Aeschlimann, PharmD, an associate professor at the University of Connecticut School of Pharmacy, in Storrs, and adjunct associate professor at UConn School of Medicine’s Division of Infectious Diseases, in Farmington, called the results from ACTT “very encouraging.” Noting that “a therapy that can potentially make patients improve quicker and get discharged from hospitals will be an important advance to decrease strain on our health care system [and] support eventual easing of social distancing measures,” he nevertheless expressed tempered enthusiasm for the drug based on the mechanism of action and limited data available at this point.

“We all would love to have seen remdesivir, or any drug for that matter,” cause mortality rates “to go from the placebo number (approximately 12%) to something like 1%, but it’s unrealistic to expect a drug only with antiviral activity to do this,” Dr. Aeschlimann said. “By the time patients need hospital care, the downstream effects of the viral infection have kicked in. We know that there’s an excess of unhealthy immune system activation, lung tissue damage, and strain on an already chronically ill patient’s heart, kidneys, liver and other vital organs.” In addition, he pointed to the “large role of hypercoagulation in the morbidity and mortality of COVID-19–infected patients.” 

However, the findings of the trial do offer some cause for optimism. The inclusion criteria “required a patient to be pretty sick,” Dr. Aeschlimann said. “So in that context, an approximately 4% reduction in mortality (an approximately 33% relative decrease) potentially could be pretty good. Although it didn’t reach our standard P value for statistical significance, it came pretty close (P=0.059). Given the reported sample size of 1,063 patients, if you play around with projected numbers, all it would take is a change in one or two deaths in each group to make that P value less than 0.05,” he noted.

Although the trial conducted in China was not supportive of remdesivir, it had an important limitation in that it was terminated early, mainly due to an inability to recruit patients once the pandemic waned there. So, Dr. Aeschlimann said, “it was severely underpowered to assess the primary end point (58% power, per the manuscript)” and did not do much to clarify the picture. 

One finding from the Chinese trial that Dr. Aeschlimann called “interesting and discouraging” was that remdesivir did not result in a “significant change in the time profiles of SARS-CoV-2 viral loads,” despite showing “potent in vitro activity” and an ability to “reduce viral loads in a primate model” of COVID-19. But “this doesn’t mean that remdesivir has no antiviral activity in humans,” he said.

He speculated that the lack of significant change in viral load time profiles could be related to two factors: the timing of initiation of therapy and the sensitivity of viral detection. Regarding the first factor, it may be that “maximum benefits would be derived from starting treatment as early as possible in the disease process.” In the Chinese trial, patients had a median of 10 days of symptoms before admission. “That may be too late in the infection process to have potent effects on viral replication,” he said. Data that Gilead released from its SIMPLE trial support that idea, “with better results in those started earlier on the drug” (see sidebar). Regarding the viral detection methods used in the Chinese trial, Dr. Aeschlimann said that “assessing and detecting amounts of shed viral RNA into the upper and/or lower respiratory tract secretions—without determination of its viability and/or infectivity potential—may not turn out to be the most sensitive or specific marker of in vivo antiviral activity.” He added that “there may be other ways that we have yet to discover/implement that could show antiviral activity.”

 

Five- and 10-Day Remdesivir Dosing Yielded Similar Efficacy Patients with COVID-19 receiving five- and 10-day courses of remdesivir achieved similar improvement in clinical status, according to topline results from a phase 3 clinical trial reported by Gilead. “These data are encouraging as they indicate that patients who received a shorter, five-day course of remdesivir experienced similar clinical improvement as patients who received a 10-day treatment course,” said Aruna Subramanian, MD, the chief of immunocompromised host infectious diseases at Stanford University School of Medicine, in California, and one of the lead investigators of the study. “While additional data are still needed, these results help to bring a clearer understanding of how treatment with remdesivir may be optimized, if proven safe and effective.” The trial—one of two multicenter, randomized, open-label, phase 3 clinical trials (called SIMPLE) that Gilead has initiated in countries with a high prevalence of COVID-19 infection—is evaluating the safety and efficacy of five- and 10-day dosing regimens of remdesivir in hospitalized patients with severe COVID-19 disease. The initial phase of the study randomly assigned 397 patients in a 1:1 ratio to receive 200 mg of remdesivir on the first day, followed by 100 mg of remdesivir each day until day 5 (n=200) or 10 (n=197), in addition to standard of care (ClinicalTrials.gov Identifier: NCT04292899). The patients in the study, who were defined as having severe COVID-19 disease, were required to have evidence of pneumonia and reduced oxygen levels but did not need mechanical ventilation at the time of study entry. An expansion phase of the study recently was added and will enroll an additional 5,600 patients, including patients on mechanical ventilation. The investigators also evaluated additional measures of clinical response and rates of adverse events (AEs) in both treatment groups. Clinical improvement was defined as an improvement of 2 points or more from baseline on a predefined 7-point scale, ranging from hospital discharge to increasing levels of oxygen support to death. Patients achieved clinical recovery if they no longer required oxygen support and medical care, or were discharged from the hospital.  In this study, the time to clinical improvement for 50% of patients was 10 days in the five-day treatment group and 11 days in the 10-day treatment group. More than half of patients in both treatment groups were discharged from the hospital by day 14 (five-day group, 60% vs. 10-day group, 52.3%; P=0.14). At day 14, 64.5% of the patients receiving five-day treatment and 53.8% of those given the 10-day treatment achieved clinical recovery. In an exploratory analysis, patients in the study who received remdesivir within 10 days of symptom onset had improved outcomes compared with those treated after more than 10 days of symptoms. The pooled data for treatment arms showed that by day 14, 62% of patients treated early were able to be discharged from the hospital, compared with 49% of patients who were treated later. The company reported that no new safety signals were identified with remdesivir across either dosing group and the drug was generally well tolerated. The most common AEs occurring in more than 10% of patients in either group were nausea (10.0% vs. 8.6%) and acute respiratory failure (6.0% vs. 10.7%) for the five- and 10-day groups, respectively. Grade 3 or higher alanine aminotransferase elevations occurred in 7.3% of patients, with 3% of patients discontinuing remdesivir due to elevated liver enzymes. The Emergency Use Authorization issued by the FDA for remdesivir requires that Gilead make fact sheets about the drug for health care providers and patients that includes information about potential AEs, including increased levels of liver enzymes and infusion-related reactions (bit.ly/2Su349P). The fact sheets also include information about drug interactions and dosing instructions.  Takeaways From the Dosing Trial  One important consideration about this study is that it included hospitalized patients infected with SARS-CoV-2 “but not yet needing critical care and/or mechanical ventilation,” noted Jeffrey R. Aeschlimann, PharmD, an associate professor at the University of Connecticut School of Pharmacy, in Storrs, and adjunct associate professor at UConn School of Medicine’s Division of Infectious Diseases, in Farmington.  In addition,  “the time to clinical improvement, based on a 6-point ordinal evaluation scale tool, was similar for both treatment groups,” he said, which lends support to use of the shorter course of therapy.  “It’s also important to note that these numbers appear to be similar to the ones described in the NIAID ACTT study,” Dr. Aeschlimann said, “so there appears to be some consistency of outcomes between these two separate trials.” Another takeaway from these data, he said, is that patients who received remdesivir within 10 days of the start of symptoms appeared to derive the most benefit.  Gilead stated it plans to submit the full data for publication in a peer-reviewed journal in the coming weeks. A second SIMPLE trial that is controlled is comparing the safety and efficacy of the same dosing regimens of remdesivir plus standard of care with standard of care alone in 1,600 patients defined as having moderate disease (ClinicalTrials.gov Identifier: NCT04292730). The results from the first 600 patients in this study are expected at the end of May.                                                                                                                                                                                                                       —S.T.

 

Production Will Need to Be Ramped Up

Although the remdesivir evidence still is preliminary, it was enough to convince the FDA to issue the EUA. As a result, Gilead will need to dramatically accelerate production to meet global requirements. The FDA “has been engaged in sustained and ongoing discussions” with the company about “making remdesivir available to patients as quickly as possible, as appropriate,” according to NIAID. 

In an open letter on Gilead’s website, CEO and Chairman Daniel O’Day noted that the company has “been ramping up production since January, working within all the constraints [of the] lengthy and complex manufacturing process” required to make the drug (bit.ly/2Yq2cH6). “Existing supply, including finished product ready for distribution as well as materials in the final stages of production, amounts to 1.5 million individual doses,” Dr. O’Day noted. Based on a 10-day course of treatment, the company had estimated that to be approximately 140,000 treatment courses, but if a five-day course turns out to be effective, as early findings from the SIMPLE trial indicate (see sidebar), that could potentially double the number of patients treated.