Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19FREE
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Visual Abstract. Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19
This randomized, placebo-controlled trial aimed to determine the overall efficacy and safety of combination therapy with 2 SARS-CoV-2 neutralizing antibodies—amubarvimab and romlusevimab—and evaluated whether there was a benefit of administration more than 5 days after symptom onset.
Abstract
Background:
Development of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti–SARS-CoV-2 monoclonal antibodies with an extended half-life.
Objective:
To assess the safety and efficacy of amubarvimab plus romlusevimab.
Design:
Randomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410)
Setting:
Nonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines.
Patients:
Adults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression.
Intervention:
Combination of monoclonal antibodies amubarvimab plus romlusevimab or placebo.
Measurements:
Nasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death.
Results:
Eight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P < 0.001). This reduction was similar between participants with 5 or less and more than 5 days of symptoms at study entry. Grade 3 or higher treatment-emergent adverse events through day 28 were seen less frequently among participants randomly assigned to amubarvimab plus romlusevimab (7.3%) than placebo (16.1%) (P < 0.001), with no severe infusion reactions or drug-related serious adverse events.
Limitation:
The study population was mostly unvaccinated against COVID-19 and enrolled before the spread of Omicron variants and subvariants.
Conclusion:
Amubarvimab plus romlusevimab was safe and significantly reduced the risk for hospitalization and/or death among nonhospitalized adults with mild to moderate SARS-CoV-2 infection at high risk for progression to severe disease.
Primary Funding Source:
National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
The COVID-19 pandemic caused by SARS-CoV-2 is ongoing, and the emergence of new variants has affected the activity of monoclonal antibody (mAb) regimens (1). Research evaluating safe and effective treatments to prevent progression to hospitalization and/or death has resulted in U.S. Food and Drug Administration (FDA) emergency use authorization (EUA) for several mAbs and direct-acting antivirals (2–8). However, 4 mAb EUAs have been withdrawn or limited because of reduced in vitro susceptibility to new variants (2, 9–11).
Amubarvimab (BRII-196) and romlusevimab (BRII-198) are recombinant human IgG1 mAbs derived from convalesced patients who had COVID-19 (Brii Biosciences, Tsinghua University, and Third People’s Hospital of Shenzhen) (12, 13). They are directed against conserved, nonoverlapping epitopes in receptor-binding domain of SARS-CoV-2 spike protein with complementary neutralizing effects in vitro (12, 13). Activity against the Omicron variant (B.1.1.529) is predicted by in vitro studies (14), with live virus data suggesting efficacy against subvariants BA.4 and BA.5 (15). Both mAbs have a triple amino acid substitution, M257Y/S259T/T261E, in the fragment crystallizable region to prolong the half-life (16, 17) and reduce binding activity against Fcγ receptors, potentially minimizing risk for antibody-dependent enhancement (12, 13). Phase 1 studies investigating the safety, tolerability, and pharmacokinetics of intravenous amubarvimab (NCT04479631) and romlusevimab (NCT04479644) (12, 13) supported further clinical evaluation (18). We report the results of a phase 2 and 3 trial of amubarvimab plus romlusevimab in nonhospitalized persons with mild to moderate COVID-19 at high risk for progression to severe disease.
Methods
Trial Design and Oversight
ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients With COVID-19) is an ongoing, multinational, randomized controlled, blinded platform trial designed to evaluate safety and efficacy of investigational agents for treatment of nonhospitalized adults with mild to moderate COVID-19. The protocol was approved by a central institutional review board, Advarra (Pro00045266) for U.S. sites (with additional local institutional review board approval as required), and by local ethics committees for non-U.S. sites. All participants provided written informed consent before undergoing study procedures.
The study included a phase 2 evaluation with prespecified “graduation analysis” to determine if investigational agents would proceed to phase 3 (details provided in the protocol). An independent data safety and monitoring board (DSMB) reviewed the study during both phase 2 and 3. For the phase 3 portion of the trial, unless otherwise recommended by the DSMB, 3 interim reviews were planned to occur after 25%, 50%, and 75% of the planned enrollment had completed 28 days of follow-up. The O’Brien and Fleming stopping guideline for efficacy and the gamma (-2) spending function for evaluating futility were implemented using the Lan–DeMets spending function approach to allow for flexibility in the timing or number of interim analyses (19). Additional details regarding stopping guidelines for efficacy and timing of interim efficacy analyses are included in section 10 of the protocol and the statistical analysis plan. The first 2 interim analyses occurred as planned. However, there was a surge in enrollment such that the second review occurred after the planned enrollment for the study had been met. On request of the DSMB, the third DSMB interim review occurred 2 weeks later. At this review, the DSMB concluded that there was overwhelming evidence of benefit and recommended early release of results while continuing blinded follow-up of all participants.
Participants and Procedures
Participants were nonhospitalized adults, aged 18 years or older, and at high risk for progression to severe COVID-19 (defined in the Supplement). All participants had a positive molecular or antigen SARS-CoV-2 test result from the upper respiratory tract, and with 1 exception, were randomly assigned within 10 days of symptom onset. Inclusion and exclusion criteria are in the Supplement and protocol.
Participants were randomly assigned 1:1 to amubarvimab plus romlusevimab or placebo in both phase 2 and 3 portions of the study, with phase 2 participants included in the phase 3 study population. In this platform trial, phase 2 included the possibility of the control group including placebos for other agents concurrently studied in phase 2 (that is, pooled or shared placebo). Randomization was stratified by time from symptom onset (≤5 or >5 days). Details about randomization are in the Supplement.
The study intervention was administered as sequential intravenous infusions of 1000 mg of amubarvimab followed by 1000 mg of romlusevimab, or equivalent volumes of saline placebo (or pooled placebo for other agents), each infused over at least 25 minutes each on study day 0. Participants were monitored for 2 hours after infusion. A detailed schedule of assessments for phase 2 and 3 portions of trial are described in the protocol.
Study Objectives and Outcome Measures
The primary outcomes for the phase 3 portion of the trial were all-cause hospitalization and/or death through study day 28 and grade 3 or higher treatment-emergent adverse events (TEAEs). Treatment-emergent adverse events of special interest included infusion reactions or allergic reactions occurring within 12 hours of infusion. Secondary symptom-related outcome measures included time to sustained symptom improvement (defined both as days from study entry to the first of 2 consecutive days with all symptoms improved or resolved and as the first of 4 consecutive days when all symptoms are scored as absent); time to self-reported return to usual health (defined as the number of days from start of investigational agents until the first of 2 consecutive days that a participant reported return to usual “pre–COVID-19” health); severity ranking (based on time-averaged total symptom scores through day 28); and progression through day 28 of 1 or more COVID-19–associated symptoms to a worse status than recorded in the study diary at study entry, before the start of the investigational agent or comparator intervention. All measures were based on a daily symptom diary completed by participants through day 28. Other key secondary outcomes were proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ), quantitative SARS CoV-2 RNA levels and area under curve (AUC) of anterior nasal swabs collected by participants at days 0, 3, 7, 14, and 28. Methods for quantitative SARS-CoV-2 RNA measurement, SARS-CoV-2 variant determination, and symptom diary assessments are provided in the Supplement. Similar virologic outcomes were assessed from site-collected nasopharyngeal swabs during the phase 2 portion of the study.
Statistical Analysis
Analyses were restricted to the modified intention-to-treat population, defined as participants who initiated the study intervention. Except for descriptive safety summaries, participants were summarized according to the treatment to which they were randomly assigned. All analyses were done on data entered by time of data freeze on 2 June 2022.
The primary composite clinical end point of hospitalization and/or death during the first 28 days of follow-up was estimated for each randomized group using Kaplan–Meier methods. The difference between groups in estimated log cumulative proportion was calculated, and variance for this difference was obtained using the Greenwood formula (20). Two-sided 95% CIs and associated P value for the test of no difference between groups were obtained.
The primary safety end point was the proportion experiencing a grade 3 or higher TEAE by study day 28 between randomized groups using log-binomial regression and summarized with a risk ratio, corresponding 95% CI, and P value based on the Wald test. A descriptive comparison between study groups (defined by actual treatment received) of all TEAEs through day 28 was also done.
The time to sustained symptom improvement and return to usual health were compared between groups using the Gehan–Wilcoxon test. Symptom severity ranking and risk for symptom progression were compared between groups using a Wilcoxon test and a χ2 test, respectively.
The proportion of participants with SARS-CoV-2 RNA below LLoQ was compared between groups across study visits using Poisson regression with robust variance adjusted for baseline (day 0) log10 transformed SARS-CoV-2 RNA level and summarized with a risk ratio and 95% CI at each study visit, and a Wald test across the multiple times. Quantitative SARS-CoV-2 RNA levels were compared between groups using Wilcoxon rank-sum tests, separately at each post-entry study visit, without adjustment for baseline value. Participant-specific AUCs were compared between groups using a Wilcoxon test.
All statistical tests used a 2-sided 5% significance level. Statistical analyses were done with SAS, version 9.4 (SAS Institute). The complete ACTIV-2 statistical analysis plan is provided.
Role of the Funding Source
The funding source had representatives on the study team and were involved in protocol development, study conduct, and analysis of the data.
Results
Study Population
A total of 847 participants were randomly assigned between January and July 2021, after which enrollment was stopped due to meeting the target. The exclusion of 30 participants from 2 sites with data integrity issues and 10 who did not receive the study intervention resulted in 807 who received the intervention and were included in the modified intention-to-treat analysis (Figure 1). Participants were enrolled from 6 countries; 397 were randomly assigned to amubarvimab plus romlusevimab and 410 to placebo (including 1 who received placebo for another agent). Eight participants randomly assigned to placebo received amubarvimab plus romlusevimab, and 7 randomly assigned to study drugs and 21 to placebo stopped treatment or discontinued study on or before day 28.
Figure 1. CONSORT flow diagram.
In this platform trial, participants randomly assigned to a placebo for other agents in phase 2 evaluation may be included in the control group for evaluating amubarvimab plus romlusevimab during phase 2. For amubarvimab plus romlusevimab, there was only 1 participant in the randomized population who received placebo corresponding to a different agent. The safety analysis population included 405 participants who initiated amubarvimab plus romlusevimab (including 8 randomly assigned to placebo) and 402 who initiated placebo. Details of the screened population are not shown in the CONSORT diagram, as screening was broad for evaluating multiple investigational agents in parallel and not specific to each agent. CONSORT = Consolidated Standards of Reporting Trials; mITT = modified intention to treat.
The phase 3 population included 221 participants enrolled in the phase 2 portion of the trial, all in the United States (Appendix Table 1). Baseline characteristics of phase 3 participants are described in Table 1. Median age of participants was 49 years, with 22% aged 60 years or older; 51% were women, 0.2% were transgender, 73% were White, and 50% were Hispanic. Fifty-one percent enrolled between 6 and 10 days of symptom onset (10% after day 8). Variant data were available for 401 of 539 participants enrolled in the United States, with 22.2% infected with Delta and the remainder with pre-Delta variants.
Clinical Efficacy
Of 807 participants in the modified intention-to-treat population, 53 were hospitalized and/or died through study day 28—nine randomly assigned to amubarvimab plus romlusevimab and 44 to placebo (Table 2 and Figure 2). The cumulative incidence of hospitalization and/or death through day 28 was 79% lower (ratio of proportions, 0.21 [95% CI, 0.10 to 0.43]; P < 0.001) among participants randomly assigned to amubarvimab plus romlusevimab (2.3%) compared with placebo (10.8%). In analyses of subgroups defined by time from symptom onset to study entry (≤5 vs. >5 days), cumulative incidence of hospitalization and/or death was lower in participants randomly assigned to amubarvimab plus romlusevimab compared with placebo regardless of timing of treatment, with hospitalization or death rates of 2.1% versus 11.0% among those enrolled within 5 days, and 2.5% versus 10.5% among those enrolled more than 5 days from symptom onset (Table 2). In sensitivity analyses, findings were similar when participants lost to follow-up before day 28 were counted as events (ratio of proportions, 0.23 [CI, 0.12 to 0.45]; P < 0.001). Through day 28 of follow-up, there were no deaths in the amubarvimab plus romlusevimab group and 8 (2.0%) in the placebo group (P = 0.008). In subgroup analysis of those with variant data available, efficacy was seen in those infected with Delta and non-Delta variants (Appendix Figure and Appendix Table 2).
Figure 2. Cumulative proportion of death or hospitalizations through day 28.
Cumulative proportion of death or hospitalization is estimated by the Kaplan–Meier method. The first occurrence of either death or hospitalization is considered as the event. Hospitalization is defined as ≥24 h of acute care, in a hospital or similar acute care facility, including emergency rooms or temporary facilities instituted to address medical needs of those with severe COVID-19 during the COVID-19 pandemic, through day 28. Deaths from any cause through day 28 are included.
Appendix Figure. Death or hospitalization through day 28 by Delta versus non-Delta COVID-19 variant.
Analyses include modified intention to treat persons enrolled in U.S. sites only. Cumulative proportion of death or hospitalization is estimated by the Kaplan–Meier method. The first occurrence of either death or hospitalization is considered as the event. Hospitalization is defined as ≥24 h of acute care, in a hospital or similar acute care facility, including emergency rooms or temporary facilities instituted to address medical needs of those with severe COVID-19 during the COVID-19 pandemic, through day 28. Deaths from any cause through day 28 are included.
Symptom outcomes are summarized in Appendix Table 3. The time to sustained symptom improvement for 2 consecutive days was similar between groups and similar for participants treated within 5 days versus more than 5 days after symptom onset. The median time to absence of symptoms for 4 consecutive days was also similar between groups. There was a trend toward a difference in median time to self-reported return to usual pre–COVID-19 health for 2 consecutive days between the amubarvimab plus romlusevimab (16 days [quartiles, 8 to >27]) and placebo (20 days [quartiles, 10 to >27]) (P = 0.059) groups. This difference was statistically significant for participants treated within 5 days but not those with greater than 5 days of symptoms at enrollment. Comparison of symptom severity rankings through day 28 showed statistically significant differences in AUC of total symptom score between groups, with a median of 2.41 (quartiles, 1.27 to 4.95) in the amubarvimab plus romlusevimab group versus 3.09 (quartiles, 1.29 to 6.46) in the placebo group (P = 0.005). Finally, the percentage of participants with progression of COVID-19 associated symptoms through day 28 was similar between groups.
Safety Analysis
The primary safety end point involved a comparison of grade 3 or higher TEAEs through day 28 by randomized group. The event rate was significantly lower in the amubarvimab plus romlusevimab group compared with the placebo group: 7.3% versus 16.1% (risk ratio, 0.45 [CI, 0.30 to 0.69]; P < 0.001).
Treatment-emergent adverse events through day 28 by actual treatment received is summarized in Table 3. There were fewer TEAEs and grade 3 or higher TEAEs reported in the amubarvimab plus romlusevimab group than in the placebo group (35.8% vs. 39.6% and 7.4% vs. 16.2%, respectively). The groups had similar frequencies of study drug–related TEAEs and TEAEs of special interest (4.2% vs. 4.0% and 1.2% vs. 1.0%, respectively, for amubarvimab plus romlusevimab compared with placebo). There were no anaphylaxis-like reactions in either group.
Virologic Outcomes
Virologic outcomes for the phase 3 portion of the trial are summarized in Table 4 and Appendix Table 4. The proportion of participants with anterior nasal SARS-CoV-2 RNA levels below LLoQ was significantly higher across all post-entry time points in the amubarvimab plus romlusevimab group compared with the placebo group (overall Wald test P = 0.004, adjusted for day 0 levels). In sensitivity analyses, this finding remained significant when participants with baseline levels below LLoQ were excluded (P = 0.001). When stratified by time from symptom onset (≤5 or >5 days), the proportion of participants with anterior nasal SARS-CoV-2 RNA levels below LLoQ was significantly higher across all post-entry time points in the amubarvimab plus romlusevimab group compared with the placebo group in those enrolled within 5 days (P = 0.006) but not those enrolled more than 5 days from onset of symptoms (P = 0.27).
Quantitative anterior nasal SARS-CoV-2 RNA levels were significantly lower in the amubarvimab plus romlusevimab group at days 3 and 7 in the overall population (P = 0.001 and 0.003, respectively) and the subset enrolled within 5 days from symptom onset (P = 0.001 and P < 0.001, respectively), with similar findings seen in a sensitivity analysis excluding those below LLoQ at day 0 (P < 0.001). There was also significantly lower viral AUC for amubarvimab plus romlusevimab versus placebo, with median of 3.90 (quartiles, 0.00 to 11.70) versus 6.15 (quartiles, 0.00 to 21.18) log10 copies/mL × days, respectively (P = 0.002).
Virologic outcomes on nasopharyngeal swabs in the smaller phase 2 population showed numerical differences favoring the amubarvimab plus romlusevimab group but no statistically significant difference in the proportion with RNA levels below LLoQ (overall Wald test P = 0.60, adjusted for day 0 levels) (Appendix Table 5). Nasopharyngeal SARS-CoV-2 RNA levels were lower for the amubarvimab plus romlusevimab group versus placebo at each time point, but a statistically significant difference was seen only at day 14 (P = 0.008) (Appendix Table 5). There was no statistically significant difference in the AUC of SARS-CoV-2 RNA levels between study groups (P = 0.55).
Discussion
The ACTIV-2/A5401 trial demonstrated the safety and efficacy of amubarvimab plus romlusevimab for treatment of COVID-19 in nonhospitalized persons at higher risk for progression to severe COVID-19. The treatment was safe, and there was a 79% reduction in progression to hospitalization and/or death, with no deaths in the amubarvimab plus romlusevimab group compared with 8 in the placebo group through day 28. The clinical benefit was similar regardless of whether therapy was given within 5 days or more than 5 days of symptom onset.
Significantly greater reductions in anterior nasal swab viral levels were seen with amubarvimab plus romlusevimab compared with placebo. However, statistically significant virologic response was only seen in those treated within 5 days from symptom onset, with attenuated differences in those treated later, and in nasopharyngeal swab data from those enrolled in the phase 2 portion of the trial. These data suggest limitations to using nasal virologic measures to predict clinical efficacy of novel compounds. Although there was no difference in time to improvement in daily tracked COVID-19 symptoms, those in the amubarvimab plus romlusevimab group did show a trend toward more rapid self-reported return to usual health, a difference driven by those enrolled within 5 days of symptom onset. Those in the amubarvimab plus romlusevimab group also reported significantly decreased symptom severity rankings over time when compared with placebo.
Four mAb regimens (bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab) were shown to reduce hospitalizations and/or death in nonhospitalized persons (3, 4, 7, 21) and initially received FDA EUA. In addition, bebtelovimab received FDA EUA on the basis of in vitro susceptibility (22). However, these agents are no longer available in the United States because of the emergence of resistant SARS-CoV-2 variants, including Omicron (9, 10). The current study is the first to show that treatment with an anti–SARS-CoV-2 mAb therapy as late as 6 to 10 days after symptom onset significantly reduces hospitalizations and/or death. Such data should not be used to suggest that treatment can be delayed, but supports that it may be of value even up to 10 days from symptom onset. In addition, the long half-life of these antibodies raises the possibility that a single infusion may also prevent reinfections (23).
A major issue for anti–SARS-CoV-2 mAbs relates to the effect of emerging variants. During this study, the highly transmissible and pathogenic Delta variant emerged. This study showed that in a subset enrolled in the United States, clinical benefit was seen in those infected with the Delta variant, consistent with reported in vitro susceptibility (12, 13). Since the current study closed to enrollment, Omicron subvariants have emerged, with in vitro data showing a lack of susceptibility to mAbs that have previously received FDA EUA (1, 14). Although this trial enrolled participants in the pre-Omicron era, there are in vitro data suggesting that Omicron (B.1.1.529) is susceptible to amubarvimab plus romlusevimab (14). Shortly after the study ended, the predominant circulating Omicron subvariants were BA.4 and BA.5, which were susceptible in vitro using a live virus assay (15). At the observed fold-change, plasma drug levels were anticipated to exceed those required for neutralization for at least 4 weeks after infusion. However, the currently predominant variants—for example, BQ.1, BQ.1.1, and XBB—have markedly reduced susceptibility to amubarvimab and romlusevimab (24, 25). It remains unknown whether future variants will be susceptible to any of the previously proven efficacious monoclonal antibody products, including amubarvimab plus romlusevimab.
Study limitations include that few enrolled participants were immunosuppressed or had received COVID-19 vaccines. In addition, enrollment preceded widespread circulation of the Omicron subvariants, and that there are likely differences in viral dynamics in the nasopharyngeal space relative to the lower respiratory tract not measured in this study. The variant analysis is limited by only including participants in United States, and substantial missing data. This study also did not assess the effect of early treatment on transmission or on long-term clinical outcomes such as postacute sequelae of SARS-CoV-2 infection.
This study shows that amubarvimab plus romlusevimab is safe and effective in reducing hospitalizations and deaths among those with mild to moderate COVID-19 at high risk for clinical progression and acquired infection before emergence of Omicron variants. The study also shows clinical benefit of amubarvimab plus romlusevimab for up to 10 days from COVID-19 symptom onset. Although initially approved in China, its utility in the United States with currently circulating Omicron subvariants is likely to be limited, although available in the future if new variants were shown to have in vitro susceptibility.
Supplemental Material
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Published In
Annals of Internal Medicine
Volume 176 • Number 5 • May 2023
Pages: 658 - 666
History
Published online: 18 April 2023
Published in issue: May 2023
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© 2023 American College of Physicians.
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Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19. Ann Intern Med.2023;176:658-666. [Epub 18 April 2023]. doi:10.7326/M22-3428
Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19. Ann Intern Med.2023;176:658-666. [Epub 18 April 2023]. doi:10.7326/M22-3428
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