An update of antispike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies,Suparna Chatterjee1, Shouvik Choudhury2, Debaleena Das1, : Indian Journal of Pharmacology

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Year : 2022 \| Volume : 54 \| Issue : 1 \| Page : 51--57

An update of antispike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies

Suparna Chatterjee¹, Shouvik Choudhury², Debaleena Das¹,
¹ Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
² Department of Pharmacology, Burdwan Medical College, Burdwan, West Bengal, India

Correspondence Address:
Dr. Suparna Chatterjee
Department of Pharmacology, Institute of Postgraduate Medical Education and Research, 244 B, Acharya J. C. Bose Road, Kolkata - 700 020, West Bengal
India

Abstract

The use of monoclonal antibodies has expanded beyond the realm of autoimmune disease and cancer therapeutics to communicable diseases. Their antiviral activities were evaluated in some diseases such as SARS MERS (Middle East Respiratory Syndrome) and Ebola. In recent times, antispike SARS-CoV-2 monoclonal antibody cocktails (casirivimab with imdevimab and bamlanivimab with etesevimab) and single agent sotrovimab have received emergency use authorization for treatment of nonhospitalized COVID-19 patients with mild-to-moderate disease at high risk of disease progression. This review summarizes their mechanism of action, salient pharmacokinetic profile, safety and clinical trial (ongoing and completed) data. Despite evidence to support its use for the indication, the high cost of these biologics may make it unaffordable for many patients, but further clinical studies on their cost-benefit profile shall provide useful information to the scientific community and patients.

How to cite this article:
Chatterjee S, Choudhury S, Das D. An update of antispike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies.Indian J Pharmacol 2022;54:51-57

How to cite this URL:
Chatterjee S, Choudhury S, Das D. An update of antispike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies. Indian J Pharmacol [serial online] 2022 [cited 2023 Oct 4 ];54:51-57
Available from: https://www.ijp-online.com/text.asp?2022/54/1/51/339910

Full Text

Introduction

We are nearly 18 months into this unprecedented global pandemic and strategies to prevent or treat the disease are still being explored. Multipronged approaches to arrest viral entry, multiplication, or alter host immune responses to facilitate quick viral clearance and prevent the onslaught of immune-related events like cytokine storm and related organ damage have been adopted. However, till date, convincing evidence of any medication, whether new or repurposed, against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with a highly favorable benefit-risk ratio is unavailable. Therefore, vaccines continue to remain the most effective immunotherapeutic strategy for COVID-19 disease prevention. The effectiveness and safety of convalescent plasma are debatable and have recently been discontinued in some countries including India where it was initially approved.[1]

The use of monoclonal antibodies (mAB) dates back to more than three decades when “muromonab CD 3” was approved for use in renal transplant patients for graft rejection.[2] Over the years, their use has expanded beyond the realm of autoimmune disease and cancer therapeutics to communicable diseases. Their antiviral activities were evaluated in some diseases like Severe acute respiratory syndrome (SARS) , Middle East respiratory syndrome (MERS) and Ebola.[3] Palivizumab, a humanized monoclonal, was approved in 1998 to prevent severe disease caused by respiratory syncitial virus in infants with high risk of the disease.[4] The extraordinary pace at which academia and industry conducted studies evaluating the efficacy and safety of anti-SARS CoV2 therapeutic neutralizing mAB is appreciable. Such efforts brought to the table some mAB cocktails or single agents with emergency use authorization (EUA) in countries such as US, France, Germany, Italy, India, and few more.[5],[6]

In May 2021, the Indian drug regulatory authority accorded restricted use authorization to the monoclonal cocktail of casirivimab and imdevimab. To provide the readers a comprehensive update about these agents, this write up features the salient pharmacokinetic/pharmacodynamic and safety profiles of antispike SARS CoV-2 antivirus mAB with EUA. In addition, an overview of the ongoing and completed trials has been included. However, we have excluded therapeutic mAB that target host cell immune response genes.

Anti SARS-CoV-2 antispike monoclonal antibodies approved for emergency use authorization

Literature search has indicated that as on May 28, 2021, there are two combinations and two single agents anti-spike mABs that have been accorded EUA.

The first agent that received EUA was bamlanivimab followed by a cocktail of casirivimab and imdevimab (November 2020). Shortly, thereafter combination of bamlanivimab with etesevimab (February 2021) and single-agent sotrovimab (May 2021) have been marketed.[7],[8],[9],[10] In India, the cocktail of casirivimab and imdevimab received restricted use authorization by CDSCO in May 2021.[11]

[Table 1] enlists the antibodies which are marketed under EUA in various countries. The EUA for bamlanivimab as a single agent was, however, revoked by US Food and Drug Administration (FDA) in April 2021 based on review of emerging scientific data wherein it was found that the frequency of SARS-CoV2 variants resistant to bamlanivimab had increased over time.[12]{Table 1}

Proposed mechanism of action

SARS-CoV-2 is a single-stranded RNA virus of the genus betacoronavirus which like other members of the same genus have 3 main categories of genes – structural, nonstructural, and accessory.[5] The viral genome encodes for four major structural proteins: the spike(S) protein having subunits, namely S1, S2; E (envelope), M (membrane), and N (nucleocapsid) proteins. S1 attaches through receptor-binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2) which is present in host cell and induces a conformational change in S2. It results in virus-host cell membrane fusion and viral entry.[6] The virus-host interaction is indeed very complex and viral entry involves interactions with several other proteins in addition to ACE2.[5] Although all proteins have been explored as potential targets in anti-SARScoV2 mAB development, the S protein has emerged as the principal one.

The anti-SARS–CoV-2 mAB are proposed to act by preventing the viral entry primarily by binding to conserved epitopes of the viral spike protein which subsequently inhibits its attachment to the host cell surface receptors.[3],[6] The cocktails currently available are all recombinant human neutralizing IgG1 mAB that binds to the spike protein and block attachment to the human ACE2 receptor.[7],[8],[9],[10] A schematic figure [Figure 1] of the proposed mechanism of action is provided.{Figure 1}

Casirivimab and Imdevimab are proposed to attach noncompetitively with the RBD of spike protein.[13] Similarly, bamlanivimab, etesevimab also attaches to distinct sites but overlapping epitopes on the RBD of the viral S-protein.[7]

It is postulated that co-administration of two antibodies at a fixed dose possibly reduces the likelihood of emergence of resistant viral strains and treatment failure while adding on to its effectiveness.[14]

Salient pharmacokinetic profile and posology

The mABs are administered as single-dose intravenous (IV) infusion and demonstrate linear pharmacokinetic profile in the recommended doses. Clinical study data reported a maximum plasma concentration (Cmax) of 196 μg/mL following 1 h of bamlanivimab IV infusion (700 mg) and 504 μg/mL for etesevimab (1400 mg). The volume of distribution of bamlanivimab is 2.87 L and 2.71 L and etesevimab-2.38 L and 1.98 L for the central compartment and peripheral compartments.[7],[8],[9],[10] The mAbs do not undergo metabolism by cytochrome P450 enzymes and undergo degradation into small peptides through catabolic pathways similar to IgG antibodies. There is a paucity of clinical data on drug disposition in renal or hepatic impairment. Dose adjustments are not recommended in renal impairment as they are unlikely to be excreted by the renal route. Bamlanivimab has a terminal elimination half-life of about 18 days, etesevimab 25 days, and casirivimab and imdevimab cocktail of 13–18 days.[7],[14] Clinical trial data suggest that dialysis may not affect pharmacokinetics of either drug.[13] The safety of these agents is yet to be established in pediatric age group (<12 years) or in pregnancy. Although clinical reproductive studies have not been conducted, it can be inferred that as these mAB are IgG1, they are likely to cross the placental barrier and a developing fetus may get exposure from the mother. However, whether this placental transfer shall offer any benefit or pose any adverse effect is yet to be evaluated.[13]

Prescribing information states that their drug interaction potentials are likely to be minimal as they are not metabolized by CYP enzymes or excreted by the kidney.[13]

The recommended dosing of the two cocktails are (a) casirivimab (1200 mg) and imdevimab (1200 mg); (b) bamlanivimab 700 mg and etesevimab (700 mg). They are administered as single dose IV infusion with 0.9% sodium chloride.[7],[13]

Indications for Use

Based on clinical trials, the cocktails have been given EUA for newly diagnosed COVID-19 (i.e., as quickly as possible after a direct viral test positive and within the 10 days of symptoms onset) nonhospitalized patients of mild-to-moderate severity but who are at high risk of disease progression like – obese (body mass index ≥35), age ≥65 years, chronic kidney disease, diabetics, on immunosuppressants, or suffering from immunosuppressive diseases, age ≥55 years with cardiovascular disease, chronic obstructive pulmonary disease or any other chronic respiratory diseases, hypertension, etc.[13]

US FDA EUA is for “the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age or older weighing at least 40 kg) who test positive for SARS-CoV-2 and who are at high risk for progressing to severe COVID-19. The authorized use includes treatment for those who are 65 years of age or older or who have certain chronic medical conditions”However, it explicitly states that the cocktails are not approved for “hospitalized COVID patients or those of oxygen therapy due to COVID or have an increased baseline oxygen requirement due to COVID in those on chronic oxygen therapy due to other comorbidities”[8]The European Medicines Agency has also approved this combination for COVID-19 patients of ≥12 years age and with COVID-19 and in a risk of progressing toward severe disease not requiring supplemental oxygen.[15]

Safety Profile

Labeled adverse reactions

The listed adverse reactions for the cocktails are hypersensitivity reactions, anaphylaxis, infusion-related reactions like chills, fever, headache, urticaria, pruritus, bronchospasm, myalgia, dyspnoea, nausea, dizziness, hypotension.[13] There is a theoretical remote chance of enhancement of immune reactions of the virus and chances of reinfection.[13]

Spontaneous adverse drug reactions (ADR) data in vigibase

[Table 2] summarizes the suspected adverse drug reactions (ADR) reports in the WHO global spontaneous drug safety database (vigibase) as on May 25, 2021. The safety reports in the database are from various countries which have varying patterns of spontaneous ADR reporting. As of date (May 25, 2021), no safety signal has been published with their use.{Table 2}

Summary of ongoing and completed clinical studies

[Table 3] enlists studies which are ongoing or have been completed as per available data in two important trial registries, the clinicaltrials.gov (www.clinicaltrials.gov) and Clinical trial registry of India (www.ctri.nic.in).{Table 3}

The approval of bamlanivimab/etesevimab was based on two placebo-controlled double-blind trials (BLAZE 1 Phase 2/3 and ongoing BLAZE 4 Phase 2) of the cocktail in COVID-19 patients with chances of high risk of progression of the disease and/or hospitalization. The results had shown that the combination had significantly decreased hospitalization or death during the follow-up period of 29 days and also reduced the viral load at the 11 days compared to placebo.[9],[16]

The approval of casirivimab and imdevimab was based on a randomized, placebo-controlled, double-blind randomized controlled trial on adults who were nonhospitalized with mild-to-moderate COVID-19 symptoms. The result showed overall reduction in viral load on day 7. The effect was more in those patients who had greater viral load than others. The study also showed reduction in hospitalization rate or visit to emergency up to 29 days following treatment initiation.[14]

Conclusion

Until specific antivirals with high efficacy and acceptable safety are available for the treatment of COVID-19, a multi-targeted approach to prevent and control the disease shall continue. By and large, vaccination has been successful in preventing severe disease and mortality. The antivirus neutralizing monoclonal antibody cocktail casirivimab and imdevimabhas recently received restricted EUA in India for mild and moderate disease. The high cost (about 60,000 Indian rupees) may not be affordable for our population at large but well designed pharmaco-economic studies would provide evidence about its cost-benefit profile. In addition, a strict monitoring system to ensure that it is used only for the labeled indication if critical else we will end up indiscriminately using such biologics. Postmarketing safety and effectiveness studies are also needed for generating further information about these biologics.

Acknowledgment

We acknowledge the National coordinating center (NCC) Pharmacovigilance Programme of India, IPC, Ghaziabad for providing us access to the WHO global drug safety database, as IPGMER is an ADR monitoring center and East zone regional center for training under the Program.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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