Noninferiority of Subcutaneous Versus Intravenous Casirivimab/Imdevimab for Outpatient Treatment of SARS-CoV-2 in a Real-World Setting

Introduction

Monoclonal antibody (mAb) therapy has emerged as one of the mainstay ambulatory treatment options for SARS-CoV-2. Utilized early in the infectious replication window, these antibodies target specific glycoproteins on the virus' structure to block viral replication.^1–3 However, resistance can quickly develop. ¹ SARS-CoV-2's unimpeded spread has resulted in its swift ability to generate escape mutations, leading to new variants immune to previous mAb targets.^1,4,5

Casirivimab/imdevimab (Regen-COV) was one of the promising mAb therapies that developed resistance with emergence of the Omicron variant. It first received Emergency Use Authorization (EUA) in November 2020 ⁶ and was utilized at the height of the Delta surge of the SARS-CoV-2 pandemic. ³ It was recommended by the Infectious Disease Society of America for outpatient treatment of SARS-CoV-2 patients at risk of deterioration to severe disease. ⁷ Following resistance to the newly widespread Omicron variant in January 2022, the EUA was amended. Use of casirivimab/imdevimab is no longer recommended in geographic regions predominated with unsusceptible variants, including Omicron. ⁶

However, existing data of casirivimab/imdevimab can still be utilized to assess effectiveness of mAbs for SARS-CoV-2. Past clinical trials show reduction in all-cause hospitalization after single intravenous (IV) infusion of casirivimab/imdevimab and relative risk reduction of infection of household contacts given subcutaneous (SC) injection.^3,8,9 Beyond effectiveness in treatment, casirivimab/imdevimab is notable for administration options; it is delivered by IV infusion or SC injection, with IV as the preferred administration route.^6,7 Although IV administration reaches higher serum concentrations sooner, ³ clinical trial data have demonstrated that both IV- and SC-administered casirivimab/imdevimab serum levels reach targeted therapeutic levels in as early as 24 hours after delivery.^3,8,10,11 Current mAb treatment options receiving EUA, including Sotrovimab, are limited to IV delivery, with alternative administration methods are actively being investigated. ¹²

A recent international prospective randomized control trial investigated SC mAb therapy for household contacts of SARS-CoV-2-infected individuals. Participants were administered SC casirivimab/imdevimab or placebo, which revealed SC casirivimab/imdevimab prevented progression to symptomatic disease in close contacts. If symptoms did arise, SC mAb therapy reduced total symptom duration and depressed viral load. ³ A separate nonpeer-reviewed head-to-head prospective cohort study comparing casirivimab/imdevimab IV and SC administration route shows promising comparable clinical outcomes at 28 days. ¹³ However, sufficient data investigating SC delivery of mAbs are lacking. ¹⁴ Further investigation is needed comparing clinical outcomes of SC versus IV. This retrospective cohort study compares hospitalization rates among patients receiving IV versus SC administration of casirivimab/imdevimab at a single institution in Arkansas.

Methods

During a SARS-CoV-2 surge in July 2021, a regional medical center switched from delivering standard IV casirivimab 600 mg and imdevimab 600 mg to alternate SC administration route at the same dose due to lower bedside nursing requirements and a significant delay in scheduling IV infusion. A retrospective cohort study compared 162 outpatients who received standard IV casirivimab/imdevimab between April 9, 2021 and August 3, 2021 to 444 outpatients who received SC casirivimab/imdevimab between July 30, 2021 and August 21, 2021 at Washington Regional Medical Center in Northwest Arkansas. Inclusion and exclusion criteria for therapy were in keeping with the Arkansas Department of Health recommendations at the time of administration. ¹⁵ Data were obtained through individual chart review and discrepancies were discussed and resolved as a group through consensus.

Comorbidities accounted for included hypertension, heart disease, chronic kidney disease (defined as stage III or greater), pulmonary disease, diabetes, immunosuppression, pregnancy, smoking history, active cancer, and prior cancer. Primary outcomes were the 30-day post-treatment rate of hospitalization and intensive care unit (ICU) care during hospitalization. Descriptive statistics and odds ratio comparing odds of hospitalization or ICU care for IV compared with SC groups were used to assess the effect of administration route on clinical outcomes. R 4.1.2 was used with statistical significance defined as p < 0.05. This study was approved through the University of Arkansas for Medical Sciences Institutional Review Board (IRB No. 273493) and the Washington Regional Medical Center Institutional Review Board (protocol 2021-010).

Results

Both the IV and SC groups were predominantly Caucasian (p = 0.3587). Both were ∼57% female (p = 0.9254), had comparable average body mass index (p = 0.3345), and between one to two comorbidities (p = 0.5668). There was a slight age difference of the groups, with the IV group averaging 58 years and the SC group averaging 55 years (p = 0.0216) (Table 1). Chi-squared tests indicated that administration route did not significantly affect the odds or rate of hospitalization or ICU care 30 days after therapy (Table 2).

Discussion

There was no increased risk of hospitalization or ICU care with SC administration compared with IV administration. These data represent real-world experience from a geographic area with low vaccination rates and high mAb therapy utilization. ¹⁶ The slightly lower age of the SC group could be due to increased awareness of mAb availability and eligibility, although the IV and SC groups had comparable numbers of comorbidities suggesting that the baseline health status of the two groups were comparable.

These data cannot account for some treated outpatients who may have been hospitalized in a different health system; however, we expect similar rates in both the IV and SC groups. Time to therapy may be a more significant determinant of clinical outcomes than administration route as the SC group may have received their therapy earlier in their course of illness due to increased access to and awareness of services over time. Further studies could investigate the effect of timing of administration on clinical outcomes through correlation of time between symptoms onset and treatment with clinical outcomes.

These preliminary findings of noninferiority support continued investigation into use of SC mAb injections as a viable alternative to IV infusions where available for treatment of SARS-CoV-2. However, caution should also be taken when extrapolating these data to other mAbs. Similar head-to-head trials could investigate if comparable noninferiority exists. This equivocal effectiveness with SC administration has been observed with mAbs in other clinical realms outside of treatment for SARS-CoV-2. Multiple oncological SC mAbs have been shown to have similar efficacy compared with their IV counterparts.^10,17,18,19

These findings warrant ongoing investigation into SC administration of future mAbs. As SARS-CoV-2 continues to evolve, resistance to existing mAbs is a likely ongoing problem. Numerous IgG mAbs are in the clinical pipeline in phase 3 clinical trials. Furthermore, ongoing research into additional immunotherapies other than IgG are under investigation, including, IgM, IgA, IgY. ²⁰ Potential future alternate route mAbs could help to curb the health care burden of the pandemic. SC administration increases access to and feasibility of mAb therapy in low-resource or high-demand settings.