The coronavirus disease 2019 (COVID-19) pandemic is ongoing and has caused more than four million deaths as of October 2021 (1). Among the therapeutic agents tested against COVID-19, neutralizing monoclonal antibody (mAb) agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were found to decrease viral loads and prevent disease progression of mild COVID-19 (2–9). On September 2021, US National Institutes of Health recommended use of anti-SARS-CoV-2 mAb regimens, including casirivimab/imdevimab (Regeneron Pharmaceuticals Inc., NY, USA), bamlanivimab/etesevimab (Eli Lilly and Company, IN, USA), and sotrovimab (GlaxoSmithKline LLC, NC, USA), to treat non-hospitalized patients with mild to moderate COVID-19 who are at high risk of clinical progression (10). In the phase III trial, casirivimab/imdevimab decreased viral load faster than placebo, and COVID-19-related hospitalization or death from any causes were significantly reduced both in 2400mg and 1200mg arm (relative risk reduction of 71.3% and 70.4%, respectively) (7). Bamlanivimab/etesevimab also exhibited significant reduction of COVID-19-related hospitalization or death from any causes (relative risk difference, 70%) (9), and sotrovimab reduced COVID-19 progression risk by 85% (8).

Regdanvimab (CT-P59, Celltrion Inc, Incheon, Republic of Korea), a mAb agent against SARS-CoV-2, was approved by the Korea Ministry of Food and Drug Safety for the treatment of mild COVID-19 patients with risk factors for progression on February 5, 2021 based on the results of in-vitro study and the interim data of a phase II/III clinical trial (6, 11), and was reviewed by European Medicines Agency on March 2, 2021 for the support of national decisions on early use (12). In that trial, the incidence of severe COVID-19 cases requiring inpatient treatment was reduced by 54% among all COVID-19 patients and 68% among patients with moderate COVID-19 older than age 50. The time for clinical recovery was 5.4 days in the regdanvimab group, which was reduced by 3.4 days compared to 8.8 days in the placebo group (13). The approval in Korea was conditioned on the success of a phase III clinical trial, which was reported to meet its endpoints in June 2021 (14). To evaluate the clinical response to regdanvimab in the real world, we conducted a retrospective cohort study evaluating the pre- and post-periods of regdanvimab treatment.

Passive immunization using mAb products require healthcare resources for intravenous administration to mild COVID-19 patients (10). To overcome such limitation, casirivimab/imdevimab added indication for subcutaneous injection based on a phase I trial (20). In the Republic of Korea, mAb agents are practically applicable to mild COVID-19 patients with risk factors for progression because those patients are managed at general hospitals where intravenous administration is available (21, 22). After the conditioned approval of regdanvimab on February 17, 2021, several COVID-19-designated hospitals began actively administering regdanvimab to indicated patients. To date, regdanvimab has been widely administered in Korean COVID-19 designated hospitals, but the data from clinical trials of regdanvimab have not been published as a full scientific article yet (13). As evaluation of the clinical efficacy of treatment modalities in a real-world setting would be especially necessary for drugs under emergency use authorizations (4), we conducted the present retrospective cohort study for scientific background for COVID-19 management.

Of note, in the multivariate analyses of the total cohort and PS-matched cohort, regdanvimab treatment was significantly associated with a decreased risk of progression to severe disease. Although a reduced risk for requiring O₂ supplementation was not statistically significant in the PS-matched cohort, a tendency favoring the regdanvimab group was noticed, consistent with the analysis of the total cohort. The need for other treatment modalities, including remdesivir, steroids, and antibiotics, was significantly lower in the regdanvimab group, and the length of hospital stay among patients who recovered without referral was also shorter in the regdanvimab group than in the supportive care group. These findings consistently indicate that regdanvimab treatment offers clinical benefit for high-risk patients. Because most mild to moderate COVID-19 patients of the Republic of Korea are managed at designated general hospitals, these primary outcomes of the present study are not identical with those of clinical trials conducted for non-hospitalized COVID-19 patients (4, 7, 9). The clinical status of COVID-19 patients who require O₂ supplementation in the present study would be similar or slightly more severe than those who require hospitalization in those trials, though indications for hospitalization were not clearly presented (4, 7, 9). Since those clinical trials did not evaluated progression to severe disease as an outcome value, the finding of the present study would additionally support effectiveness of mAb agents for mild to moderate COVID-19 patients.

However, the progression rate in this study population was low (18.4% for O₂ supplement and 9.6% for progression to severe disease in the supportive care group), because regdanvimab treatment is approved for early COVID-19 patients who have relatively broad risk factors for disease progression. The proportion of COVID-19-related hospitalization was much lower in the clinical trials of other mAb agents for non-hospitalized patients (control arms, 3.2–7.0%) (7, 9). To figure out whether a high-risk subgroup might gain more benefit from regdanvimab treatment, we investigated the common risk factors for progression in our analyses of the total cohort and supportive care group. Among the various clinical variables, SpO₂ < 97% and CRP level > 1.5 mg/dL were common risk factors for progression, and the progression rate in the higher-risk sub-group (of patients with either of those factors) was 28.5% for O₂ supplementation and 14.4% for progression to severe disease. Meanwhile, in the lower-risk sub-group (of patients without any of these two factors), progression rates to O₂ supplement and to severe disease were 6.1% and 2.4% respectively, which were similar to those treated with regdanvimab. Adding those factors to the treatment guidelines could increase the cost-effectiveness, but a certain proportion of patients would lose their treatment opportunity. The appropriate indication for mAb treatment thus needs to be adjusted based on the outbreak situation and healthcare resources.

Although only five patients in the regdanvimab group (2.1%) progressed to severe disease, we also conducted multivariate analyses to identify the risk factors for regdanvimab failure. It was difficult to find consistent factors between the two primary endpoints, but the statistically significant factors of late admission, decreased oxygenation, thrombocytopenia, and SIRS might be associated with progressed disease. The time interval between symptom onset to admission or regdanvimab treatment was associated with O₂ supplementation, consistent with previous cohort study conducted at USA (4), but administration time interval was not associated with progression to severe disease in the present cohort. These findings suggest that early administration of regdanvimab would be important, but other unmeasured factors may have stronger association with regdanvimab failure. Since potential virulence factors associated with viral mutation was not evaluated in the present analysis, a larger cohort study with viral sequencing needs to be conducted to clearly elucidate the factors involved in regdanvimab failure.

The present study has several limitations. First, we retrospectively evaluated patients before and after regdanvimab became available. Even though the management in the outbreak setting could be different, it is less likely because study population were admitted at early time point after symptoms onset and managed at the same hospital. During the study period, management for mild COVID-19 patients did not change, and the community-based spread of SARS-CoV-2 variants of concerns (VOCs) was not significant in the Republic of Korea (23). The two hospitals participated in the present study have been dedicated for mild and moderate COVID-19 patient care since the first (March 2020) and second (June 2020) domestic outbreak, respectively, and the medical resources and management protocols were well-stabilized before the start of present study (December 2020). Nevertheless, basic demographic factors such as age, sex, and underlying disease could be variable according to the outbreak situation and seasons. To overcome that limitation, we enrolled a control group more than two times larger than the regdanvimab group in a short period and performed multivariate analyses and PS matching. Second, the cohort study was conducted in two general hospitals, and outcomes after patients were referred to tertiary care centers could not be investigated. During hospitalization at these general hospitals, only one patient in the supportive care group died who could not be referred to a tertiary care center due to insufficient capacity. A large, nation-wide cohort study is needed to evaluate the final outcomes of patients whose disease progressed despite regdanvimab treatment. Last, although the study patients were confirmed with COVID-19 with SARS-CoV-2 RT-PCR, whole genome sequencing (WGS) to detect viral mutation was not performed. Although the effectiveness of mAbs could be different against VOCs, VOCs were not dominant during the study period in the Republic of Korea. The healthcare authority selectively performed WGS to detect viral mutation for risk groups such as immigrants from VOC-endemic countries and individuals exposed to VOCs. In the present cohort, only one case in the regdanvimab group was reported to be infected with alpha variant. Although he progressed to severe disease despite regdanvimab treatment, it was difficult to interpret the impact of a single case of VOC. Follow-up studies against VOCs need to be conducted during a VOC-dominant outbreak period with sequencing of entire study population.

In conclusion, in a retrospective cohort study evaluating high-risk COVID-19 patients, regdanvimab treatment within seven days of symptom onset was associated with decreased risk of progression to severe disease.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Samsung Medical Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

JiL, JeL, J-HK, SS, and KP contributed to the conceptualization. JiL, JeL, J-HK, MH, HK, SC, YDL, JS, and SS, and KP contributed to the investigation. J-HK and SS contributed to the statistical analysis. KP contributed to the supervision. J-HK, SS, and KP contributed to the writing, review, and editing. All authors contributed to the article and approved the submitted version.

This work was supported by Research Program funded by the Korea Disease Control and Prevention Agency (#2021-ER1906-00).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.