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

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.

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.[56]

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.[78910] 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

List of approved monoclonal antibodies targeted against severe acute respiratory syndrome-coronavirus-2 as on May 28th, 2021

Name	Target	Status	EUA approved indication and dose	Developer
Bamlanivimab	Spike protein	EUA (US FDA) in November 2020; Revoked on April 16, 2021	For mild-to-moderate nonhospitalized patients 700 mg as single infusion	Eli Lilly and Co
Bamlanivimab plus Etesevimab	Spike protein	EUA (US FDA) on February 2021	For mild-to-moderate disease in adults and children ≥12 years and body weight 40 kg who are at risk of progression to severe disease 700 mg Bamlanivimab with 1400 mg Etesevimab as single infusion	Eli Lilly and Co
Casirivimab plus Indevimab	Spike protein	EUA (US FDA) on November 2020 CDSCO (India) granted EUA in April 2021	For mild-to-moderate nonhospitalized patient Casirivimab with Imdevimab (1200 mg each) single IV infusion	Regeneron Pharmaceuticals Inc
Sotrovimab	Spike protein	EUA (US FDA) on May 2021 EMA rolling review ongoing	For mild-to-moderate disease (direct SARS COV2 viral test positive) in adults and children ≥12 years and body weight ≥40 kg who are at risk of progression to severe disease 500 mg single IV infusion	GlaxoSmithKline Limited
Regdanvimab	Spike protein	EMA recommended its use; Rolling review going on	Positive patients who do not require oxygen supplements but at high risk 40 mg/kg single IV infusion	Celltrion Healthcare Hungary Kft

EMA: European medicines agency, SARS COV2: Severe acute respiratory syndrome-coronavirus-2, EUA: Emergency use authorization, US FDA: United States Food and Drug Administration, IV: intravenous

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.[36] 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.[78910] A schematic figure [Figure 1] of the proposed mechanism of action is provided.

Figure 1

Schematic mechanism of action of antispike monoclonal antibodies against severe acute respiratory syndrome coronavirus 2

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.[78910] 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.[714] 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.[713]

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 suspect adverse drug reactions reports in Vigibase

Drug (active ingredient)	Countries from where reported	Total reports in Vigibase	Top 4 listed ADR
Casirivimab + Imdevimab	USA, Italy, Germany, Czechia, France, Belgium	462	Chills, pyrexia, dyspnea, infusion related reactions
Bamlavimab + Imdevimab	USA, Italy, France	74	Dyspnea, infusion related reactions, chills, pyrexia
Bamlavimab	USA, Italy, France, Germany, Czechia, Serbia	4031	Dyspnea, pyrexia, chills, oxygen saturation decreased

Caveat: Reports in the database do not necessarily imply causation. ADR: Adverse drug reaction, AUC: Area under the curve, IM; Intramuscular, Cma: Maximum plasma concentration, Tmax: Time taken to achieve maximum concentration

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

List of some trials on monoclonal antibody cocktails in the treatment of COVID-19

Study ID	Study type and status	Study population	Study arms and enrolled subjects	Clinical endpoints	Microbiological endpoints	Safety endpoints
Trials with interim results
NCT04427501 (BLAZE 1)	Randomized double-blind sequential assignment phase 2/3 Recruiting	Ambulatory to moderate	Bamlanivimab versus Bamlanivimab with Etesevimab versus placebo (3160 subjects)	COVID-related hospitalization or death; symptoms resolution or improvement	Change of viral load from baseline at day 11	Serious adverse events
NCT04425629	Randomized parallel design quadruple masked phase 2/3	Non hospitalized RT PCR positive patients	Casiri+Imdevimab Versus placebo (Ongoing trial with 6420 subjects; Interim analysis of 275 subjects published)	patients with ≥1 medically attended visit	Change of viral load from baseline at day 11	Serious adverse events
Ongoing trials registered in clinicaltrials.gov or ctri.nic.in
NCT04840459	Nonrandomized parallel design open-label phase 2 (recruiting)	Mild-to-moderate nonhospitalized patient	Bamlinimab versus Casirivimab-Imdevimab (1000 patients)	Minimize and/or eliminate the number of patients from progression to severe disease from mild cases
NCT04790786 (UPMC OPTIMISE-C19 trial)	Randomized parallel design open-label phase 3 (recruiting)	Confirmed COVID-19 case	Bamlanivimab versus Casirivimab-Imdevimab Versus Bamlanivimab + Etesevimab (5000 patients)	Alive and free from hospitalization; organ support free days; all-cause mortality at 28 days	Viral load and antibody titer
NCT04426695	Randomized parallel design quadruple masked phase 1/2 (active, not recruiting)	Hospitalized Adult patients with COVID-19	REGN10933 + REGN10987 versus Placebo (6900 patients)	Incidence of death or required mechanical ventilation;	Time-weighted average Change from baseline in viral load	Infusion-related reactions; hypersensitivity reaction; death
NCT04852978	Randomized parallel design open-label phase 2 (not yet recruiting)	In adult volunteers	REGN10933 + REGN10987 and Moderna mRNA-1273 vaccine (180 patients)		ID50 titer of vaccine-induced neutralizing antibodies to the S protein of SARS-CoV-2	Treatment-emergent adverse events
NCT04666441	Randomized parallel design quadruple masked phase 2 (active, not recruiting)	Different dose regimens in adult outpatients with SARS-CoV-2 infection	REGN10933 + REGN10987 versus placebo (1164 patients)		Time-weighted average daily change from baseline in viral load	Treatment-emergent adverse events
NCT04452318	Randomized parallel design quadruple masked phase 3 (active, not recruiting)	Asymptomatic healthy adults and adolescents in contact with positive cases	REGN10933 + REGN10987 versus placebo (3750 patients)	Proportion of participants who subsequently develop Signs and symptoms	Symptomatic RT-qPCR confirmed SARS-CoV-2 infection Participants with a viral load >4	Treatment-emergent Adverse events
NCT04656691 (United)	Single group assigned Phase 4 trial Completed	Mild-to-moderate at home patients	Bamlanivimab (4000 patients)	Hospitalization rate		Adverse event after infusion
NCT04796402 (B-EPIC)	Randomized parallel design open-label phase 4 Recruiting	Non hospitalized positive patients	Bamlanivimabvs standard care (576 patients)	Hospital admission for > 24 h; mortality		Treatment-emergent adverse events
NCT04701658 (BLAZE 5)	Nonrandomized parallel design open-label phase 2 Active, not recruiting	Mild-to-moderate cases	Bamlanivimab (3000 patients)	Hospitalization rate or visit to emergency department or death		Treatment-emergent adverse events
NCT04748588 (CATCO-NOS)	Randomized parallel design open-label phase 4 Recruiting	Nosocomial COVID-19	Bamlanivimab (648 patients)	In-hospital death, death following discharge, requiring ICU or mechanical ventilation		Treatment-emergent adverse events
NCT04411628	Randomized parallel design double-blind phase 1 completed	Hospitalized patients	LY3819253 (24 patients)		Change in viral load	Serious adverse event
NCT04497987 (BLAZE 2)	Randomized parallel design double-blind phase 2 Active, not recruiting	Prevention of COVID-19 in Nursing home residents and staffs	LY3819253 and LY3832479 versus Placebo (5000 subjects)	Percentage become positive or requiring hospitalization or death		Treatment-emergent adverse events
NCT04518410 (ACTIV 2)	Randomized parallel design triple-blind phase 2/3 Recruiting	Outpatient positive cases	Bamlanivimab versus AZD7442 versus SNG001 versus Camostatvs Placebo (2000 patients)	Duration of symptoms or hospitalization	Quantification of virus	Serious adverse effects
NCT04634409 (BLAZE 4)	Randomized parallel design double-blind phase 2 Recruiting	Mild-to-moderate cases	LY3819253; LY3832479; Placebo; VIR-7831; LY3853113	Symptoms resolution or improvement; hospitalization or death;	Change in viral load	Treatment-emergent adverse events
NCT04723394 (TACKLE)	Randomized parallel design double-blind phase 3 (recruiting)	Non hospitalized positive cases	AZD7442 versus placebo (1700 patients)	Prevention of death or progression to severity	Levels of SARS-CoV-2 RNA on day 29	Treatment-emergent adverse events
NCT04913675	Randomized, multi-center, open-label phase 3 (not yet recruiting)	Mild-to-moderate high-risk nonhospitalized patients	Sotrovimab (VIR 7831) 500 mg IM versus 250 mg IM	Progression of disease	Cmax, Tmax, AUC	Treatment-emergent adverse events
NCT04545060 (COMET-ICE)	Randomized, Multi-center, quadriple blind phase 2/3 (not yet recruiting)	Early treatment in mild cases	VIR 7831 versus placebo (1360 patients)	Progression of disease on day 28	Cmax, Tmax, AUC	Treatment-emergent adverse events
NCT04779879 (COMET-PEAK)	Randomized, Multi-center, quadriple blind phase 2 (recruiting)	Non hospitalized mild-to-moderate cases	VIR 7831 (40 patients)			Treatment-emergent adverse events
NCT04501978 (TICO)	Randomized, parallel group, triple-blind phase 3 (recruiting)	Hospitalized cases	LY3819253 versus AZd7442 versus VIR 7831 versus Remdesivirvs Placebo	Recovery or complications or all-cause mortality		Treatment-emergent adverse events

SARS-CoV-2: Severe acute respiratory syndrome-coronavirus-2, RT-qPCR: Real-time-quantitative polymerase chain, mRNA: Messenger RNA, AUC: Area under the curve, IM: Intramuscular

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.[916]

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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.