This phase 4 PMS study investigated regdanvimab in patients with high-risk mild or moderate COVID-19, confirmed by RT-PCR. Data from 3036 patients support the tolerability and effectiveness of regdanvimab in clinical practice. PMS studies are an integral component of the regulatory process and are mandated by the MFDS in Korea for any new approved drug product [34,35,36, 40]. Although randomised controlled trials are the gold standard for evaluating drug efficacy and safety, the strict eligibility criteria and restricted patient numbers can mean that factors such as rare ADRs and important drug–drug interactions are missed [34, 40]. PMS studies are especially important following the rapid development and approval of COVID-19 vaccines and therapeutics, and the additional data may help inform treatment decisions in the clinic [33, 41].

Analysis of regdanvimab treatment in this large real-world patient population did not reveal any new safety concerns. In total, AEs and ADRs were reported in 684 (22.5%) and 363 (12.0%) of patients, respectively. The most common ADR was increased liver function tests, observed in 62 (2.0%) of patients. Unexpected ADRs occurred in 293 (9.7%) of patients. Discontinuation of regdanvimab administration due to AE was in all cases related to IRR and was observed in only 9 patients (0.3%). IRRs are known to be commonly associated with mAb infusion [42]. In the present study, pruritus, urticaria, rash, and dizziness—AEs often related to IRRs—all occurred in < 1% of patients. Of the 3036 patients treated with regdanvimab, 2 reported serious ADR (anaphylactic shock and cerebral infarction), both of whom recovered.

The overall safety findings of this PMS study were consistent with those of previous controlled studies of CT-P59 and other therapeutic anti-SARS-CoV-2 antibodies [20, 21]. In the phase 3 study of regdanvimab (CT-P59), treatment-emergent AEs (TEAEs) were reported in 30.4% of patients. The most frequently reported treatment-related AEs in the regdanvimab group were liver enzyme increases and hypertriglyceridemia (both 1.1%). IRRs were reported for 0.6% patients treated with regdanvimab [20]. ‘Real-world’ evidence for other SARS-CoV-2 mAb therapies is limited, although evidence from clinical trials demonstrates comparable instances of TEAEs (up to 28.1%), with IRRs reported to be among the most frequent observations (up to 4.2%) [43, 44].

In general, similar to our PMS study, reports of serious adverse reactions following anti-SARS-CoV-2 mAb treatment in the clinic are few [45], and there are conflicting reports in the literature regarding the effect of mAb treatments for COVID-19 on cardiovascular events. Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) revealed an increase in hypertension events with casirivimab/imdevimab, bamlanivimab, bamlanivimab/etesevimab, and bebtelovimab, and ischaemic heart disease for casirivimab/imdevimab and bamlanivimab, but no association between cardiovascular events and treatment with sotrovimab or tixagevimab/cilgavimab [46]. In contrast, analysis of VigiBase, the safety database of the WHO, discovered an increased risk for arterial and venous thromboembolic events with tixagevimab/cilgavimab as compared with other anti-SARS-CoV-2 mAbs [47]. In our PMS study, no substantial new safety signals were identified. This is notable considering that cardiovascular disease was categorised in 1199 (39.5%) patients at baseline as one of the high-risk criteria, and only a small number (0.4%) of cardiac disorder ADRs were reported.

This PMS study suggests real-world effectiveness of regdanvimab for the treatment of mild-to-moderate COVID-19. A higher proportion of patients (12.5%) experienced disease progression compared with the 3.1% of patients who received regdanvimab in the phase 3 trial [20]. However, this should be considered in the context of the additional criteria used to define disease progression in the PMS study versus the phase 3 study. Progression for the PMS study included supplemental oxygen therapy, mechanical ventilation, extension of the hospitalisation period or re-admission after discharge, ICU monitoring, remdesivir administration, and death. In the phase 3 study, progression was defined as clinical symptoms requiring hospitalisation, oxygen therapy, or death. The proportions of patients who received regdanvimab and required supplemental oxygen therapy (9.3%) or hospital re-admission (9.9%) were higher in the PMS compared with the phase 3 trial (2.3% and 2.4%, respectively) [20]. According to treatment guidelines in South Korea, all SARS-CoV-2 confirmed positive cases are admitted to a residential treatment centre, and patients who progress to symptomatic COVID-19 are admitted to hospital for treatment and isolation. So, the PMS study was based on a hospitalised patient population where oxygen therapy can be given promptly and easily to patients who are in need, whereas the phase 3 study was conducted in ambulatory patients from 13 countries where differences in country-specific practices could have had an impact. In addition, extension of hospitalisation was also included as a progressive criterion in the PMS study, which might have been prolonged according to investigator’s judgement in addition to the aggravation of COVID-19 and could also be confounded by non-COVID-19 factors, such as comorbidities. Despite these differences, the mortality rates between the PMS study (0.1%) and phase 3 studies (0.2%) were similar [20].

Retrospective studies conducted in South Korea under similar conditions have reported a similar effectiveness of regdanvimab in preventing disease progression or reducing the need for supplemental oxygen compared with this PMS study [25, 26, 32]. In a retrospective cohort study with a primary endpoint of proportion of patients with mild-to-moderate COVID-19 who deteriorated with SpO2 ≤ 94% on room air up to day 28, 13.4% (17/127) progressed in the regdanvimab cohort compared with 39.5% (75/190) in the standard of care cohort [25]. A propensity-score-matched retrospective study reported that 7.1% (8/113) of patients with mild-to-moderate COVID-19 treated with regdanvimab progressed to severe/critical COVID-19 or died within 28 days of treatment compared with 16.1% (26/161) in the control group [26]. In another retrospective study, 8.1% (19/234) of patients with high-risk mild COVID-19 treated with regdanvimab required supplemental oxygen and 2.1% (5/234) progressed to severe disease compared with 18.4% (100/544) and 9.6% (52/544) of patients in the supportive care group, respectively [32]. Overall, the PMS study results align with those reported from a recent meta-analysis of randomised controlled and retrospective studies of regdanvimab. This meta-analysis found that morbidity (in terms of supplemental oxygen use and/or progression to severe disease) and mortality were improved for regdanvimab versus control [48].

The rate of COVID-19 disease progression was reduced if regdanvimab treatment was administered promptly, within 3 days of symptom onset. Notably, the subgroup analysis of patients who required oxygen therapy indicated that the median time from symptom onset to regdanvimab infusion exceeded 3 days in moderate patients. When considered in contrast with the generally early (≤ 3 days) administration of regdanvimab in patients with mild disease, this suggests that the higher rate of disease progression in moderate patients could be attributed to the delayed administration of regdanvimab following onset of symptoms. A similar observation was made in Japan following casirivimab/imdevimab administration: a sharp increase in disease progression was noted after day 5 of symptom onset [49]. Both studies support the early administration of mAb treatment for COVID-19.

The effectiveness of regdanvimab against the delta variant should be noted, especially as this variant has been associated with higher intrinsic severity and progression than other variants of SARS-CoV-2 [50]. However, these data should be interpreted with caution given the varying numbers of patients in each subgroup and the fact that for most (74.4%) patients the variant was unknown due to the sample survey method performed by the KDCA, although at the time of this study the delta variant was the predominant circulating variant in South Korea. Between July and December 2021, the delta variant accounted for almost 100% of COVID-19 cases in South Korea [39]. During the same period, a total of 2452 (81%) patients in this PMS study received regdanvimab, and therefore it is highly likely that many of the patients in the Unknown variant group were also infected with the delta variant. A retrospective study of over 700 patients with the delta variant treated with regdanvimab does support a clinical benefit for regdanvimab against this variant [51]. The proportion of patients requiring ICU monitoring after treatment with regdanvimab (0.3%) is lower than that observed in an analysis of a large real-world cohort of high-risk patients (n = 10,775) treated with bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab during the delta surge (1.0%, 1.0%, and 0.4%, respectively) [52]. A real-world effectiveness study in the United States of early mAb treatment for mild-to-moderate COVID-19 in over 2500 patients found lower rates of hospitalisation or death for a range of mAbs and presumed variants of SARS-CoV-2 (based on treatment date and circulating variants) compared with a propensity-score-matched non-treated control group (4.6% vs 7.6%, respectively) [53]. Only two patients in the PMS study were known to have been infected with the omicron variant, so it is difficult to make any conclusions with respect to the effectiveness of regdanvimab against omicron. In vitro studies have described a reduced sensitivity of neutralising antibodies, including regdanvimab, to omicron variants [54,55,56].

The emergence of further SARS-CoV-2 variants is to be expected, and the development of combination therapy strategies may be required to overcome possible resistance to mAbs [8]. Antibody cocktails have been used in the clinic, and more are in development, providing an important treatment option [8]. As described above, regdanvimab is not inferior to other mAbs in terms of safety and efficacy. Therefore, when considering single prescriptions or future antibody cocktails for treating COVID-19, regdanvimab can be included as an option.

This large phase 4 study in over 3000 patients implies that regdanvimab could be effective and tolerable in routine clinical practice. As all patients were prospectively observed in an inpatient setting, the possibility of under-reporting might be minimised. However, there are some limitations. Due to the open-label nature of the study, no comparison can be made to untreated patients. The study was conducted in a limited number of sites in South Korea only. In addition, the SARS-CoV-2 variant was unknown for the majority of patients. Overall, only 147 (5%) eligible patients in this study were diagnosed with COVID-19 during the omicron-dominant period.