The Bay Area biotech company reports that the Remdesivir treatment resulted in clinical improvement in 68% of patients in a cohort analysis of 53 patients hospitalized with severe complications of COVID-19 who were treated with the investigational antiviral remdesivir on an individual compassionate use basis. In an international cohort, no new safety signals were identified as well. Compassionate use data does have limitations, and multiple Phase III clinical trials are ongoing to determine the safety and efficacy of remdesivir for the treatment of COVID-19.
As published in the New England Journal of Medicine, the promising results cannot be taken to mean the investigational product is efficacious or safe for the treatment of COVID-19—the drug is not yet licensed or approved anywhere.
The Compassionate Use Program
Gilead has been offering access to remdesivir on an emergency basis to qualifying patients with severe complications of COVID-19 who couldn’t enroll in a clinical study. In total, over 1,800 patients have been treated with remdesivir through individual compassionate use protocols since January 25, 2020.
This Study’s Cohort
This cohort evaluated from 53 patients in the United States, Europe, Canada and Japan who received at least one dose of remdesivir on or before March 7. 2020 through Gilead’s compassionate use program. All patients were hospitalized with severe acute respiratory SARS-CoV-2 infection and either an oxygen saturation of 94% or less, or a need for oxygen. The median duration of symptoms before initiation of remdesivir was 12 days. The majority of the patient were men (75%) over the age of 60 years with comorbid conditions, such as hypertension, diabetes, hyperlipidemia and asthma. Combined all three of these factors have been associated with adverse outcomes of COVID-19.
The treatment course included a 10-day course of remdesivir, consisting of a 200 mg loading dose administered intravenously on day 1, followed by 100 mg daily for the remaining nine treatment days. Of the 53 patients included in the analysis, 75% received the full 10-day course of remdesivir; 19% received 5-9 days of treatment, and 6% received fewer than 5 days of treatment.
The program included no prespecified endpoints. The physicians quantified/tracked rates of key events such as change in oxygen support requirements, hospital discharge, adverse events leading to discontinuation of remdesivir treatment and mortality. The analysis evaluated the proportion of patients with clinical improvement defined as live discharge from the hospital and/or a clinical improvement of at least two points from baseline on a six-point scale reflecting hospitalization and oxygen support status as recommended by the World Health Organization R&D Blueprint Group.
This data does not originate from a clinical trial. Rather it derives from a compassionate use program offered to those hospitalized with COVID-19 that are in bad condition. For example, of the 53 patients, 64% were on mechanical ventilation at baseline, including four patients also on extracorporeal membrane oxygenation (ECMO). Treatment with remdesivir resulted in an improvement in oxygen support class for 68% of patients over a median follow-up of 18 days from the first does of remdesivir. Over half of patients on mechanical ventilation were extubated and nearly half of all patients were discharged from the hospital following treatment with remdesivir reported its maker in a press release.
Post 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 (HR: 0.33 [95% Cl 0.16, 0.68]) and among patients at least 70 years of age (HR vs. <50 years: 0.29 [95% Cl 0.11, 0.74]).
The reported mortality rate for this cohort landed at 13%. The mortality group was higher in the subgroup of patients on invasive ventilation (18%), compared with patients on noninvasive oxygen support (5%). Gilead reported in their press release that factors physicians observed associated with an increased risk of mortality included age greater than 70 (HR vs. <70 years : 11.34 [95% Cl 1.36, 94.17]) and higher baseline serum creatinine levels (HR per mg/dL: 1.91 [95% Cl 1.22, 2.99]) indicating reduced kidney function.
Additionally, mid to moderate liver enzyme (ALT and/or AST) elevations (23%) were observed in this cohort. No additional safety signals were observed during short-term remdesivir therapy.
Limitations of this Data
First and foremost, compassionate use data are considerably limited—the sample size are too small; additionally limiting the scientific impact include the relatively short duration of follow-up, as well as potentially missing data due to the nature of the program and lack of randomized control group. Given the limitations of this data set and subsequent analysis, data from ongoing, randomized clinical studies of remdesivir are needed to provide a scientifically robust understanding of the clinical impact of the therapy. Other limitations are included in the published results.
On this note, Jonathan D. Grein, MD, Director of Hospital Epidemiology, Cedars-Sinai Medical Center, Los Angeles and lead author of the study results, noted, “Currently there is no proven treatment for COVID-19. We cannot draw definitive conclusions from these data, but the observations from this group of hospitalized patients who received remdesivir are hopeful.” Howeve,r the investigator pointed to the true requirement for results from random controlled trials that would validate any potential conclusions.
Ongoing COVID-19-focused Clinical Trials
Gilead’s ongoing Phase III clinical trials include the SIMPLE studies, in countries with high prevalence of COVID-19. The study’s sponsor (Gilead) expects results from the SIMPLE study in patients with rare disease this month (April), followed by data from the SIMPLE study in patients with moderate disease in May.
Moreover, Gilead is supporting other clinical trials led by other organizations, such as two studies conducted in Hubei Province, China. Of interest, Gilead was informed that the study in China in patients with severe disease was terminated early due to low enrollment; the company awaits publication of these data to enable in-depth review of the results. The study in China in patients with mild-to-moderate disease is ongoing. A global study of remdesivir led by NIAID continues to enroll patients and data from this study are anticipated in May. Finally, additional studies of remdesivir and other investigational treatments for COVID-19, based on a master protocol by the World Health Organization, have also begun to enroll patients worldwide.
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