Casirivimab – Imdevimab for patients with mild COVID-19

Definition of mild illness:

Symptomatic (any acute COVID-19 related symptoms)
AND respiratory rate <24/min
WITHOUT pneumonia or hypoxia

A conditional recommendation is one for which the panel is less confident about the balance between desirable and undesirable effects of the intervention, or other aspects, such as cost and feasibility.

Definition of mild illness:

Symptomatic (any acute COVID-19 related symptoms)
AND respiratory rate <24/min
WITHOUT pneumonia or hypoxia

Risk factors

1.  Age >50 years

2. Obesity, defined as body mass index >30

3. Cardiovascular disease, including hypertension

4. Chronic lung disease, including asthma

5. Chronic metabolic disease, including diabetes

6. Chronic kidney disease, including those on dialysis

Casirivimab/Imdevimab (REGEN-COV™) antibody cocktail is an investigational product developed by Regeneron pharmaceuticals as a therapeutic agent. Therapeutics that remain effective against emerging SARS-CoV-2 variants of concern (VOCs), which evade immunity from prior SARS-CoV-2 infection, vaccination, and some monoclonal antibodies (3,4,5) are the need of the hour. REGN-COV™ is a cocktail made up of two noncompeting, neutralizing human IgG1 antibodies that target the receptor binding domain of the SARS-CoV-2 spike protein, thereby preventing viral entry into human cells through the angiotensin-converting enzyme 2 (ACE2) receptor.

In mild COVID patients with > 1 risk factor and without hypoxia, REGEN-COV™ antibody cocktail at a dose of 600/600mg was evaluated within 10 days of symptom onset. Moderate quality evidence revealed that REGEN-COV™ in doses of 1.2g,2.4g and 8.0g reduced hospital admission. In addition, low quality of evidence revealed that it may reduce length of stay. However, mortality was not reduced with any dose of REGEN-COV™ though the evidence was of very low quality. It did not also reduce progression to invasive mechanical ventilation with doses of 1.2g and 2.4g but the evidence was again of very low quality. It was also noted that REGEN-COV™ did not cause any major adverse effects suggesting that it is safe. However, it is an expensive drug and needs to be prudently used to maximize cost effectiveness.  Hence this drug needs to be used cautiously in a population that is likely to benefit maximally i.e., those who are high risk of disease progression

Date of latest search: 22nd June 2021

Date of completion & presentation to Expert Working Group: 29th June 2021

Date of planned review: 29th December 2021

Evidence synthesis team: Hanna Alexander, Naveena George, Richard Kirubakaran, Bhagteshwar Singh and Priscilla Rupali

The Antibody Expert Working Group met on 29th June 2021 to consider Casirivimab and Imdevimab combination 1.2g as a treatment for COVID-19. Conflict of interest declarations were reviewed by the Steering Committee; none were found to be relevant to Casirivimab and Imdevimab.
A summary and then more detailed explanations of the Expert Working Group's judgements follow.

Problem

The COVID-19 pandemic in India, has resulted in more than 30 million infections and 0.39 million deaths, wreaking havoc on the country's health system. During the second wave believed to be due to the delta variant, the country experienced a significant health crisis due to a lack of intensive care unit beds, oxygen, and skilled manpower. This resulted in many irrational and experimental treatment interventions. Casirivimab and Imdevimab an antibody cocktail was developed by Regeneron pharmaceuticals as an experimental therapy which would be effective in patients across different categories of severity even when the infections were caused by variant or mutant strains. Studies have been done in 3 categories of severity -asymptomatic, mild out-patients and in the severe-critical category. With so many therapeutic options now available it becomes incumbent upon us as a community to define which population would maximally benefit from this drug keeping costs in mind. This expensive drug is now available in India in the dose of 1.2g (costing Rs 60,000) and it would be prudent to synthesize evidence to promote judicial use of the same. The group judged the problem to be of utmost priority.

Desirable effects

The panel discussed the anticipated desirable effects of the drug in covid-19. It was noted that the drug reduced progression to hospital admission in individuals with more than one risk factor and that was considered to be significant as that would definitely reduce requirements for advanced hospital care However, the effect size is low. Length of stay was found to be 1.4 days lower in REGEN-COV™ group vs placebo (1.2 vs placebo) which also the group felt was important in the midst of an acute shortage of beds. The median time to resolution of Covid-19 symptoms was also 4 days shorter vs placebo (10 vs 14 days; p6 log copies or if seronegative at baseline there was a drop in 1 log copies in the intervention arm as compared to placebo. There is no impact on progression to Invasive mechanical ventilation.

Undesirable effects

The panel felt that there was very little evidence to suggest that the undesirable effects are substantial. In the evidence reviewed there were very few adverse events overall and also those requiring interruption of the intervention.

Certainty of evidence

Using GRADE methodology, the group rated the certainty of evidence as moderate for progression to hospital admission and serious adverse events; low certainty for length of stay and very low certainty for mortality, progression to Invasive mechanical ventilation, admission into intensive care unit, infusion related adverse events and events leading to drug interruption. The panel felt that the overall certainty of evidence reviewed was low.

Values

The panel reviewed the outcomes that were studied and concluded that there is no important uncertainty or variability on how much people would value these.

Balance of effects

The panel felt that the balance of effects favors the intervention. The group felt that the trend favored the intervention since there is moderate certainty evidence that the intervention may reduce hospital admissions and length of stay in mild disease with few adverse events. The group felt that this was a significant effect as it could potentially free up hospital beds for those at a high risk of progression.

Resources required

The panel felt that the resources required to implement this intervention are large as the cost also factors the drug cost and the resources required to administer this drug safely as an intravenous infusion in a healthcare setting while maintaining all the infection control precautions.

Certainty of evidence of required resources

The panel felt that no studies reporting this were reviewed by the group but the clinicians in the group were aware of the cost and hence felt that there was high certainty of evidence for required resources to implement this intervention.

Cost effectiveness

Published evidence was not consulted for this judgment. The work group acknowledged that implementation of this intervention might vary among patients, hospital administrators and clinicians in different economic classes of patients due to the considerably large cost of the drug itself and the resources required.

Equity

The working group felt that the use of the intervention would definitely reduce equity. This is an expensive intervention and hence it is likely to create inequity between those who can afford it versus those who cannot, and in places where it is available freely versus where it is not.

Acceptability

The panel felt that the acceptability of the intervention among different stakeholders would vary because of the clinical efficacy stems from one trial which might lead to some reluctance but also the involved costs.

Feasibility

The panel felt that the feasibility of implementing this intervention varies depending on the stakeholder and all the factors discussed above should be carefully considered.

Casirivimab Imdevimab is an antibody cocktail which has shown to reduce hospital admission when used in mild COVID-19 infection in those patients with more than 1 risk factor for disease progression. This has been found in a single randomized trial done in the USA. There are other trials underway in this subgroup of patients. This intervention needs to be delivered intravenously over one hour and hence likely will require a health care system/clinic for drug administration with appropriate infection control protocols in place. In addition, this drug is quite expensive even if the lowest dose of efficacy is chosen which would be 1.2g; the cost and system charges are likely to be out of reach of the common man. Hence judicious use of this drug in the appropriate clinical setting is crucial. At this point, only the intravenous route is advised in patients with mild COVID-19 illness and since 2.4g is almost equivalent in efficacy to the 1.2g in most places the 1.2g dose is recommended commonly. There has been some concern that with mutating variant strains that this drug may have reduced efficacy, however evidence is slowly emerging that this antibody cocktail maintains its efficacy even in the presence of the current circulating variant strains (6). Various pharmaceutical companies have obtained permission for this drug to be licensed and marketed in India as well (7).

Being a protein moiety, though the reported drug related reactions were very low, anaphylaxis and other allergic reactions have been reported.  The costs of implementing this drug are considerable and therefore it’s widespread use in the Indian setting will not be practical or feasible.  However, the use should be definitely be considered in select sub-groups, where there are no cost constraints or in clinical settings where it would be considered cost effective. Hence, in the mildly symptomatic group with significant comorbidities or > 1 risk factor, the drug could be considered in those who can afford it if used within 7 days of symptom onset.

This drug is used only in those with mild illness in a dose of 1.2g intravenously to prevent hospital admissions and reduce length of stay. Though higher doses of 2.4g and 8.0g were also evaluated they offered no additional benefit to a dose of 1.2g in this severity subgroup. The 2.4g dose in addition also reduced admission or progression to critical or intensive care.

Though antibody status was evaluated in this study, the benefits of reduction in hospital admission and decrease in length of stay seemed to be irrespective of antibody status. The viral load reduction and time to clinical recovery seemed to be faster in those found to be seronegative as compared to the seropositive individuals.

Viral load difference in those with a baseline of > 6 log copies and < 6 log copies were also evaluated and symptom resolution was significantly quicker in those given the intervention with the effect being pronounced in the former.

This conditional recommendation for use of 1.2 gm of the casirivimab imdevimab cocktail may be revisited with emerging evidence. The group will continue to monitor new data about efficacy of the cocktail against variants including the delta and delta plus variant and whether an increase in dose of the cocktail is warranted. The emergence of data about efficacy of the cocktail in patients with multiple risk factors or a combination of risk factors with clinical symptoms with results of lab investigations may allow more cost-effective use of the drug. With increasing availability of the drug in India, cohort studies about clinical outcomes and drug adverse effects are likely to be published which the group will need to evaluate to arrive at recommendations which are contextualized to the Indian setting with the attendant cost constraints.

Several interventions like steroids and IL-6 inhibitors have been shown to decrease mortality in moderate, severe and critical categories of COVID-19 infections. However, most of these interventions have been studied as an add on to steroids and have not been evaluated separately.

1. Studies to determine if Casirivimab Imdevimab combination is cost effective in mild COVID-19 infection.

2. Defining the optimal high risk group where this drug could be given to obtain maximal therapeutic benefit.

3. Use of this drug in the various risk groups to evaluate the efficacy of this drug

4. Continued surveillance to ensure sustained efficacy of this drug in the presence of new evolving mutational variants.

1. Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N Engl J Med [Internet]. 2020 Dec 17 [cited 2021 Jun 3]; Available from: https://www.nejm.org/doi/10.1056/NEJMoa2035002
2. Commissioner O of the. Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19 [Internet]. FDA. FDA; 2020 [cited 2021 Jun 29]. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19.
3. Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ 2021;372:n579.
4. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 2021.
5. Xie X, Liu Y, Liu J, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat Med 2021.
6. Regeneron EUA HCP Fact Sheet 06032021. FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF REGEN-COVTM (casirivimab and imdevimab) accessed from https://www.fda.gov/media/145611/download
7. Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19 | Cipla [Internet]. [cited 2021 Jun 29]. Available from: https://www.cipla.com/press-releases-statements/roche-receives-EUA-India-investigational-antibody-cocktail-casirivimab-Imdevimab-covid.

Covid Management Guidelines India Group - Anti-body Working Group. Casirivimab – Imdevimab. Covid Guidelines India; Published online on August 11, 2021; URL : https://indiacovidguidelines.org/casirivimab-and-imdevimab-regn-covtm/ (accessed ).