Use of REGEN-COV in children after heart transplantation for treatment and post-exposure prophylaxis of COVID-19.

COVID-19 pandemic continues to evolve and new variants like Delta and Omicron have been discovered. REGEN-COV is a recombinant human monoclonal antibody to the spike protein of SARS-CoV-2 which received emergency use authorisation for treatment and post-exposure prophylaxis in patients with high risk of progression to severe disease. We review our experience with use of REGEN-COV in paediatric heart transplant patients.

Covid 19 Pandemic: An Overview

In the 1930's the corona virus was first identified as a highly contagious chicken respiratory virus. Two human coronaviruses were later identified, the human coronavirus 229E causing the flu and secondly the human coronavirus OC43. Others are also important as SARS-CoV. In late 2019 the outbreak of Pneumonia occurred in the Chinese city of Wuhan which was investigated as a result of the corona virus, renamed as 2019-nCoV by the World Health Organization (WHO) and. now called as SARS-CoV-2. The WHO has identified the global health problem as an epidemic. Respiratory droplets produced during coughing and sneezing are the main means of transmission of COVID-19. Infection with COVID-19 in an infected person may remain undetected. Common symptoms of fever and dry cough are less common in the production of sputum, fatigue and in some cases may be dyspnoea or shortness of breath. The COVID-19 virus is a type of RNA virus, the outer envelope containing a lipid bilayer in which various proteins are synthesized such as membrane (M), envelope (E) and spike (S). Hand washing, coughing, social isolation, wearing a face mask in public, disinfection areas, and isolation are various ways to prevent the disease. The diagnosis of COVID-19 can be made on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) tests. There are currently no antiretroviral drugs approved for COVID-19, only symptomatic and supportive treatment is used to treat people with this viral infection. Drugs that have been approved for the purpose of treating other viral infections are under investigation. Vaccination is an ultimate prevention and protection;few vaccines are given emergency approval and some are in progressive development phase in various countries to prevent this deadly pandemic.

Use of Casirivimab and Imdevimab for the Treatment of COVID-19.

The authors present three cases of unvaccinated coronavirus disease 2019 (COVID-19) patients who exhibited symptoms of fever, sore throat, nausea, diarrhea, congestion, and headache. Although they refused COVID-19 vaccination, they presented for the casirivimab and imdevimab monoclonal antibody cocktail, which resulted in the resolution of all symptoms. The authors describe the mechanisms and importance of monoclonal antibody treatment for high-risk and unvaccinated patients infected with SARS-CoV-2.

A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection.

Antiviral therapies are integral in the fight against SARS-CoV-2 (i.e. severe acute respiratory syndrome coronavirus 2), the causative agent of COVID-19. Antiviral therapeutics can be divided into categories based on how they combat the virus, including viral entry into the host cell, viral replication, protein trafficking, post-translational processing, and immune response regulation. Drugs that target how the virus enters the cell include: Evusheld, REGEN-COV, bamlanivimab and etesevimab, bebtelovimab, sotrovimab, Arbidol, nitazoxanide, and chloroquine. Drugs that prevent the virus from replicating include: Paxlovid, remdesivir, molnupiravir, favipiravir, ribavirin, and Kaletra. Drugs that interfere with protein trafficking and post-translational processing include nitazoxanide and ivermectin. Lastly, drugs that target immune response regulation include interferons and the use of anti-inflammatory drugs such as dexamethasone. Antiviral therapies offer an alternative solution for those unable or unwilling to be vaccinated and are a vital weapon in the battle against the global pandemic. Learning more about these therapies helps raise awareness in the general population about the options available to them with respect to aiding in the reduction of the severity of COVID-19 infection. In this 'A Guide To' article, we provide an in-depth insight into the development of antiviral therapeutics against SARS-CoV-2 and their ability to help fight COVID-19.

Persistent SARS-CoV-2 Infection in a Patient with Nephrotic Syndrome under Rituximab Therapy: Successful Treatment with a Combination of Remdesivir and Monoclonal Antibodies.

Rituximab is an effective treatment for frequently relapsing/steroid-dependent nephrotic syndrome, but there is concern about infections caused by humoral immunodeficiency. We herein report a case of prolonged (>7 weeks) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 24-year-old man with minimal-change disease treated with rituximab developed SARS-CoV-2 infection. The clinical response to remdesivir was soon transiently abolished. Treatment with casirivimab and imdevimab (REGEN-COV) monoclonal antibodies in combination with remdesivir resulted in complete clearance of the infection. The REGEN-COV antibody cocktail may improve the outcome of SARS-CoV-2 infection in patients with humoral immunodeficiency.

Timing of REGEN-COV administration and progression to severe COVID-19.

INTRODUCTION: Several clinical trials have demonstrated that REGEN-COV (casirivimab and imdevimab) decreases the risk of hospitalization and death among COVID-19 patients. However, these trials did not evaluate the optimal timing of its administration, and evidence is limited regarding the relationship between the timing of administration and progression to severe COVID-19 among patients who receive REGEN-COV in a real-world setting. We examined the association between the timing of REGEN-COV administration and progression to severe COVID-19 among patients who received REGEN-COV in Japan. METHODS: We included a total of 342 COVID-19 patients (37 hospitals) who received REGEN-COV between July 19 and September 30, 2021. We calculated the difference between the date of symptom onset and the date of administration as an indicator of the timing of REGEN-COV administration and determined progression to severe COVID-19 after REGEN-COV administration. We conducted a logistic regression analysis, adjusting for potential confounders. RESULTS: The proportion of cases progressing to severe COVID-19 increased daily from symptom onset and sharply increased from day 5 of onset. The early administration (days 0-4) decreased the risk of progression to severity compared with late administration (after day 5), with an adjusted odds ratio of 0.29 (95% confidence interval: 0.11-0.56). CONCLUSIONS: The early administration of REGEN-COV was associated with a decreased risk of progression to severe COVID-19 when the delta variant was dominant. The present epidemiological findings indicate that this monoclonal antibody therapy should be implemented very early in the clinical course probably even for emerging variants such as omicron BA.2.

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

Monoclonal antibody (mAb) therapy has emerged as one of the mainstay treatment options for SARS-CoV-2. To improve speed of delivery and decrease bedside nursing needs, subcutaneous (SC) delivery of mAbs has been explored as an alternative to standard intravenous (IV) administration. To date, data regarding the effectiveness of SC compared with IV mAb are lacking. This retrospective cohort analysis conducted between April 2021 and August 2021 compared hospitalization rates among patients receiving IV versus SC administration of casirivimab/imdevimab (Regen-COV) at a single institution in Arkansas. Casirivimab/imdevimab was a promising mAb therapy utilized during the height of the Delta variant surge of the SARS-CoV-2 pandemic. Before resistance developed by the Omicron variant, casirivimab/imdevimab was utilized for outpatient treatment of SARS-CoV-2 patients at risk of deterioration. Primary outcomes of this investigation were the 30-day post-treatment rate of hospitalization and intensive care unit (ICU) care during hospitalization. There was no increased risk of hospitalization or ICU care with SC administration compared with IV administration. As SARS-CoV-2 continues to mutate into variants such as Omicron and develop resistance to existing mAbs, these preliminary findings of noninferiority of SC versus IV warrant ongoing investigation into SC administration of other mAbs.

Outcomes of pregnant patients treated with REGEN-COV during the COVID-19 pandemic.

BACKGROUND: Pregnant patients with SARS-CoV-2 infection are at increased risk for severe disease including hospitalization, intensive care admission, ventilatory support, and death. Although pregnant patients were excluded from investigational trials for pharmacologic treatments for COVID-19 illness, the National Institutes of Health treatment guidelines state that efficacious treatments should not be withheld from pregnant patients. An infusion of casirivimab and imdevimab (REGEN-COV), a monoclonal antibody therapy, was shown to reduce the risk of COVID-19-related hospitalization or death from any cause and resolved symptoms and reduced SARS-CoV-2 viral load more rapidly than placebo. In July of 2021, the Food and Drug Administration released an Emergency Use Authorization for REGEN-COV. Although pregnant persons were not included in the original trials, given the higher risk of morbidity and mortality in the pregnant population, our institution offered REGEN-COV to our pregnant patients beginning in August of 2021. Side effects after REGEN-COV administration are rare and thought to be secondary to COVID-19 rather than REGEN-COV. OBJECTIVE: This study aimed to track safety and clinical outcomes in unvaccinated pregnant patients who received REGEN-COV and to compare these outcomes with those of a contemporary cohort of patients who tested positive for SARS-CoV-2 and were eligible but did not receive REGEN-COV. Our hypothesis was that REGEN-COV administration during pregnancy is safe, and that pregnant persons who received REGEN-COV would experience less severe COVID-19 respiratory illness, with decreased length of hospital stay, rates of intensive care unit admission, and need for oxygen and other COVID-19 therapeutics. STUDY DESIGN: This is a retrospective cohort study of pregnant patients who either tested positive for SARS-CoV-2 or had a known exposure to a COVID-19-positive person, and were therefore eligible for REGEN-COV at our institution. Within this cohort, we compared those who received REGEN-COV with those who did not between March and October of 2021 at Grady Memorial Hospital in Atlanta, Georgia. The main outcomes studied were perinatal outcomes, safety data, and the clinical course of SARS-CoV-2 infection. RESULTS: From March to October of 2021, 86 pregnant people tested positive for SARS-CoV-2 via real-time polymerase chain reaction or had a confirmed exposure. In this group, 36 received REGEN-COV and 50 did not. There were no instances of infusion rate adjustment or discontinuation, anaphylaxis, or death among individuals who received REGEN-COV. One individual experienced worsening shortness of breath >24 hours after administration, which was classified as an infusion-related reaction. There were no significant differences in perinatal outcomes, length of hospitalization, rates of intensive care unit admission, additional pharmacologic treatment for COVID-19, or oxygen requirement between the 2 groups. CONCLUSION: Administration of REGEN-COV is safe in pregnancy and did not increase adverse maternal, neonatal, or obstetrical outcomes. There was not a statistically significant difference in COVID-19-related outcomes in our high-risk population. Given the likely safety of this drug in pregnancy and its known benefits in the nonpregnant population, we advocate for the continued use of this therapy and encourage the development of future studies to enroll a larger and more diverse cohort to explore its efficacy further.

REGEN-COV antibody combination in patients with lymphoproliferative malignancies and SARS-CoV-2 infection.

Patients with lymphoproliferative diseases are at high risk for SARS-CoV-2-related complications and mortality. The role of casirivimab and imdevimab (REGEN-COV), a neutralizing antibody cocktail, to treat immunocompromised hemato-oncological patients with SARS-CoV-2 disease 2019 (Covid-19) remains unknown. Here, we present our clinical experience on the outcome of 15 hematological patients treated with REGEN-COV for SARS-CoV-2 infection. Most patients failed to respond or achieved low antibody titer after 2-3 doses of BNT162b2 mRNA vaccine. All patients experienced clinical improvement with no mortality within a median follow-up of 70 days. In conclusion, early administration of REGEN-COV to high-risk hematological patients may prevent clinical deterioration and mortality from SARS-CoV-2 infection. The effectiveness of neutralizing antibodies may vary depending on the virus variants and in particular with the omicron variant (B.1.1.529).

[Experience with REGEN-COV for COVID-19 complicated pregnancies.]

妊娠はcoronavirus disease 2019(COVID-19)の重症化リスクとされるが、胎児への影響から使用できる治療薬に限りがある。本邦で特例承認として薬事承認を受けたカシリビマブ及びイムデビマブ(REGEN-COV)は軽症から中等症Iの発症早期の患者に対して有用である。今回当院でCOVID-19合併妊娠11例に対してREGEN-COVを使用した。非使用群11例と比較し、臨床症状の改善までの期間や退院基準を満たすまでの期間を短縮した。また投与に伴う有害事象は認めなかった。REGEN-COVはCOVID-19合併妊娠に対して有用であった。(著者抄録)

Preclinical discovery and development of the casirivimab + imdevimab cocktail for the treatment of novel coronavirus infection: the rise and fall.

INTRODUCTION: The ongoing COVID19 pandemic represents an unprecedented opportunity to test the feasibility of monoclonal antibody (mAb) therapies against respiratory viruses. While many hurdles were easily predictable (e.g. time to develop, scalability, and economic sustainability), mAb cocktails (i.e. the combination of two mAbs) were finally deployed in 2021, one year after the beginning of the pandemic. Of them, the REGN-COV-2 cocktail was likely the most successful experience and contributed at saving lives at the time of the wave sustained by the Delta variant of concern (VOC). AREAS COVERED: Herein, the authors review the preclinical and clinical history of the casirivimab + imdevimab cocktail for the treatment of novel coronavirus infection. The authors furthermore provide the reader with their perspectives on this cocktail including its current place in the treatment armamentarium. EXPERT OPINION: Unfortunately, results from clinical trials highlighted a very limited efficacy in inpatients; furthermore, the current evidence with regards to its lack of effectiveness against the current dominant VOC (omicron) suggests a very limited use of these drugs in the future. In the authors' opinion, this story reminds us of the limitations of mAb therapies in pandemic settings, and of the inferiority of monoclonal versus polyclonal antibody-based therapeutics in such scenarios.

Impact of Antibody Cocktail Therapy Combined with Casirivimab and Imdevimab on Clinical Outcome for patients with COVID-19 in A Real-Life Setting: A Single Institute Analysis.

BACKGROUND: Recent data from clinical trials suggest that antibody cocktail therapy, which combined casirivimab and imdevimab, is linked to the reduction of the risk of hospitalization or death among high-risk patients with COVID-19. However, it remains unclear how effective the therapy is in a real-life clinical practice. METHODS: We retrospectively analyzed patients with COVID-19 with high-risk factors who underwent the antibody cocktail therapy, compared with those who were not given the cocktail therapy while being isolated in nonmedical facilities during the same period. RESULTS: Data from 55 patients who received the antibody cocktail therapy and 53 patients with initial isolation in nonmedical facilities were analyzed. A total of 22 (41.5 %) of 53 patients staying in isolation facilities were eventually hospitalized and received medical interventions. By contrast, 13 (23.6 %) of 55 patients who received the antibody cocktail therapy subsequently underwent further medical interventions. In multivariate analysis, the antibody cocktail therapy significantly reduced the need for further medical interventions by 70 % compared with isolation (odds ratio=0.30, 95%CI [0.10-0.87], p=0.027). Patients with percutaneous oxygen saturation 96% or higher were significantly favoured for the therapy and had an advantage. CONCLUSION: The results of this study indicate that the antibody cocktail therapy is associated with reducing burden on hospitals during the COVID-19 pandemic.

Updated Guidance on Use and Prioritization of Monoclonal Antibody Therapy for Treatment of COVID-19 in Adolescents.

BACKGROUND: Starting in November 2020, the US Food and Drug Administration (FDA) has issued Emergency Use Authorizations (EUAs) for multiple novel virus-neutralizing monoclonal antibody therapies, including bamlanivimab monotherapy (now revoked), bamlanivimab and etesivimab, casirivimab and imdevimab (REGEN-COV), and sotrovimab, for treatment or postexposure prophylaxis of Coronavirus disease 2019 (COVID-19) in adolescents (≥12 years of age) and adults with certain high-risk conditions. Previous guidance is now updated based on new evidence and clinical experience. METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacotherapy, and pediatric critical care medicine from 18 geographically diverse US institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on a review of the best available evidence and expert opinion. RESULTS: The course of COVID-19 in children and adolescents is typically mild, though more severe disease is occasionally observed. Evidence supporting risk stratification is incomplete. Randomized controlled trials have demonstrated the benefit of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific monoclonal antibody therapies in adults, but data on safety and efficacy in children or adolescents are limited. Potential harms associated with infusion reactions or anaphylaxis are reportedly low in adults. CONCLUSIONS: Based on evidence available as of August 31, 2021, the panel suggests a risk-based approach to administration of SARS-CoV-2 monoclonal antibody therapy. Therapy is suggested for the treatment of mild to moderate COVID-19 in adolescents (≥12 years of age) at the highest risk of progression to hospitalization or severe disease. Therapeutic decision-making about those at moderate risk of severe disease should be individualized. Use as postexposure prophylaxis could be considered for those at the highest risk who have a high-risk exposure but are not yet diagnosed with COVID-19. Clinicians and health systems should ensure safe and timely implementation of these therapeutics that does not exacerbate existing healthcare disparities.

Successful Clearance of 300 Day SARS-CoV-2 Infection in a Subject with B-Cell Depletion Associated Prolonged (B-DEAP) COVID by REGEN-COV Anti-Spike Monoclonal Antibody Cocktail.

A 59-year-old male with follicular lymphoma treated by anti-CD20-mediated B-cell depletion and ablative chemotherapy was hospitalized with a COVID-19 infection. Although the patient did not develop specific humoral immunity, he had a mild clinical course overall. The failure of all therapeutic options allowed infection to persist nearly 300 days with active accumulation of SARS-CoV-2 virus mutations. As a rescue therapy, an infusion of REGEN-COV (10933 and 10987) anti-spike monoclonal antibodies was performed 270 days from initial diagnosis. Due to partial clearance after the first dose (2.4 g), a consolidation dose (8 g) was infused six weeks later. Complete virus clearance could then be observed over the following month, after he was vaccinated with the Pfizer-BioNTech anti-COVID-19 vaccination. The successful management of this patient required prolonged enhanced quarantine, monitoring of virus mutations, pioneering clinical decisions based upon close consultation, and the coordination of multidisciplinary experts in virology, immunology, pharmacology, input from REGN, the FDA, the IRB, the health care team, the patient, and the patient's family. Current decisions to take revolve around patient's follicular lymphoma management, and monitoring for virus clearance persistence beyond disappearance of REGEN-COV monoclonal antibodies after anti-SARS-CoV-2 vaccination. Overall, specific guidelines for similar cases should be established.

The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies.

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting.