Casirivimab – Imdevimab (REGEN-COV™) for hypoxic patients with moderate, severe or critical COVID-19

Definition of moderate illness

• Pneumonia (clinical or radiological) OR hypoxia (SpO2 <94% in adults with no underlying lung disease)
• AND respiratory rate ≤30/min
• AND SpO2 ≥90% on room air

Definition of severe illness:

Pneumonia with ANY ONE of the following:

• respiratory rate >30/min
• severe respiratory distress
• SpO2 <90% on room air
• NO invasive or non-invasive respiratory support needed

Definition of critical illness:

• Requirement for high-level respiratory support: noninvasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
• OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
• OR sepsis
• OR shock

A conditional recommendation is one for which the desirable effects probably outweigh the undesirable effects (weak recommendation FOR an intervention) or undesirable effects probably outweigh the desirable effects (weak recommendation AGAINST an intervention) but appreciable uncertainty exists. This implies that not all will be best served by this recommendation and decisions can be made by the patient and caregiver based on patient values, resources and setting with a clear understanding of the ensuing harms and benefits.

Definition of moderate illness

• Pneumonia (clinical or radiological) OR hypoxia (SpO2 <94% in adults with no underlying lung disease)
• AND respiratory rate ≤30/min
• AND SpO2 ≥90% on room air

Definition of severe illness:

Pneumonia with ANY ONE of the following:

• respiratory rate >30/min
• severe respiratory distress
• SpO2 <90% on room air
• NO invasive or non-invasive respiratory support needed

Definition of critical illness:

• Requirement for high-level respiratory support: noninvasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
  •  OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
  •  OR sepsis
  •  OR shock

Rapid COVID-19 Antibody tests

Antibody tests can indicate that an individual has been exposed to the SARS CoV2 virus in the past and has mounted an immune response against it. Hence a positive result in an antibody test indicates that this this individual has been exposed to SARS COV2 virus in the past and has mounted an immune response against it. A negative antibody test indicates that the individual has not mounted an immune response against SARS CoV2 virus. This drug is only recommended in those with a negative antibody test (seronegative). Only antibody tests validated by ICMR should be used and interpreted in accordance with ICMR guidelines dates 12 February 2021 (12) https://www.icmr.gov.in/pdf/covid/kits/Antibody_based_tests_12022021.pdf

The clinical efficacy of monoclonal antibodies (mAbs) in COVID-19 is believed to be related to direct binding of the virus and neutralization of the infected host cell. Alternatively they may bind to viral antigens expressed on the surface of infected cells and stimulate antibody dependent phagocytosis and cytotoxicity via the Fc portion of the mAbs(1). The clinical benefit of mAbs is likely to be in early disease where the individual is unable to mount a robust pathogen specific immune response. This has been demonstrated in use of mAbs in outpatients with COVID-19 (2). However, it has been noted that some individuals may be antibody negative or have lost antibodies in those who present with severe disease. Therefore, it is possible that in individuals who are antibody negative there may be some evidence of clinical benefit even in those who are hospitalized with severe disease. The Recovery trial (3) studied the monoclonal antibody cocktail Casirivimab-Imdevimab at a dose of 4gm + 4gm  in those hospitalized with moderate to severe COVID-19 illness requiring oxygen support. In the seronegative patients critical outcomes including mortality, progression to non-invasive or invasive mechanical ventilation or discharged alive from hospital all favored the antibody cocktail. This modest benefit seemed more pronounced when used in <80 years of age, when used <7 days from symptom onset and those in early disease (on low flow oxygen).Considering that, seronegative status is what determines this modest benefit, the high cost and generalizability may preclude its use in the majority of the population. However in a closely selected group of patients who have not mounted an immune response against COVID-19 this high dose antibody cocktail REGEN-COV™ may be beneficial.

Date of latest search: 03rd July 2021

Date of completion & presentation to Expert Working Group: 06th July 2021

Date of planned review: 06th January 2022

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

Please note that this summary of findings table presents results for seronegative patients only, i.e. those with no detectable antibodies to SARS CoV2.

Evidence to decision – REGEN-COV™  8gm for moderate (hypoxia), severe and critical COVID-19 illness.

Summary of judgements

The Antibody Expert Working Group met on 6^th July 2021 to consider Casirivimab and Imdevimab combination (REGEN-COV™ ) 8gm 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, which has resulted in more than 30 million illnesses and 0.39 million deaths, has wreaked havoc on the country's health system. The country is experiencing a significant health crisis due to a lack of intensive care unit beds, oxygen, and skilled people. This has resulted in many irrational and experimental treatment interventions, such as the use of Casirivimab and Imdevimab in combination in all severity of patients across the country in patients hospitalized with Covid-19, with no clear indication or evidence of which subgroup of the population or disease severity the drug is effective for. The group judged the problem to be of utmost priority.

Desirable effects

The group discussed the anticipated desirable effects of REGEN-COV™ 8gm in covid-19. They agreed that the drug will be effective in seronegative patients who are hypoxic (Oxygen Saturation< 93%). The absolute effect needs to consider that the baseline risk in Indian population is low. Having considered this the effect size will be considered for different mortality rates.

Undesirable effects

The group concluded that there was insufficient data to demonstrate that the negative impacts are significant. There were very few events leading to adverse events in the evidence evaluated, and both groups had the same number of incidents.

Certainty of evidence

Using GRADE methodology, the evidence synthesis team rated the certainty of evidence as Moderate for mortality, progression to non-invasive ventilation and invasive mechanical ventilation; low certainty for progression to NIV/IMV and progression to organ support (renal replacement therapy) in seronegative patients. The group methodologist proposed that the evidence be lowered as well, because the baseline risk in our population is minimal. Because mortality, progression to NIV, and IMV are critical outcomes, the panel deemed the overall certainty of evidence is moderate.

Values

The group reviewed the evidence and concluded that there is no significant uncertainty or variability in how the outcomes are valued by the various stakeholders.

Balance of effects

The group favored the intervention as it had moderate certainty evidence of benefit and very few undesirable effects demonstrated.

Resources required

The group believed that the resources needed to implement this intervention are significantly high, as the drug is expensive and is delivered intravenously and considerably high resources are needed to securely give the drug in a healthcare facility protecting the healthcare workers and other patients.

Certainty of evidence of required resources

The group believed that no studies reporting this had been evaluated by the group, but because the physicians in the group were aware of the expense, they considered there were confident of the resources required to implement this intervention.

Cost effectiveness

Although no published research was utilized to make this decision, the expert working group stated that due to the drug's high cost and resources involved to administer the same, this intervention may be utilized differently by clinicians, administrators, as well as patients from different socioeconomic groups as well as health care settings. Hence the group felt that the cost effectiveness may vary.

Equity

The group concluded that using the intervention would definitely reduce equity. This is a costly intervention overall and it is likely to create inequalities between those who can afford it and those who cannot, as well as between private and public health care sectors.

Acceptability

The group predicted that different stakeholders' reactions to the intervention would differ. It is contingent on who will bear the financial burden. Hence the group felt that acceptability would vary among patients, clinicians and administrators.

Feasibility

The group felt that the practicality of implementing this intervention varies according to cost, health-care setting, and availability of resources.

The recommendations being made are primarily from a single randomized trial done in the United Kingdom. Casirivimab and Imdevimab antibody cocktail from the review of evidence seems to be cost effective and useful only in seronegative individuals. It is believed to reduce mortality, progression to non-invasive and invasive mechanical ventilation when used within 7 days of symptom onset or relatively early in illness along with usual care including steroids. The reported drug related reactions were very low and no clear cut drug interactions have been reported in the trials thus far. However, it would be prudent to be prepared to handle anaphylaxis and other allergic reactions. Casirivimab and Imdevimab in the recommended dose of 8g in the hypoxic moderate to critical group is not available in India, however clinicians are beginning to use 3 vials of 2.4g which is being marketed in India based on CDSCO approval.

Since the actual costs and resources required to administer this drug are huge, therefore its widespread use in the Indian setting will not be practical or feasible.  In addition, an antibody test which is validated and recommended by the Indian Council of Medical Research (7,8,12)is advised with a swift turnaround time to enable appropriate administration of this drug, which can be a challenge in most settings. However, in certain situations where costs are less of a consideration it may be of some benefit in selected sub-groups who are unable to mount a swift and adequate immune response of their own against COVID-19. So while it may work in those with no detectable antibodies against COVID-19 whether we can extrapolate to a benefit in immunosuppressed individuals remains to be seen.

There has been concern that this drug may not be effective in infections caused by variants, however this has been dispelled as data indicates that this drug is effective even against prevailing variant strains causing moderate to critical COVID-19 infection (9). In India the second wave of COVID-19 illness has been attributed to the delta variant which has now spread to different parts of the world causing another wave of infections(10).

In addition, various studies have revealed that the seropositivity rate in various communities in India vary from 30-60% (ref) and hence judicious administration where it is likely to be most likely to be beneficial is advised (11). Though the optimal use of this drug may be further modified as evidence emerges, hospitals need to make clear explicit guidelines as to when this drug should be administered taking into account the onset of symptoms, severity of illness, antibody status considering the cost implications.

Disaggregated subgroup data was not available for pregnancy, co morbidities and immunosuppression and hence at this point it is not possible to comment whether there are specific benefits or harms in this subgroup with the use of this antibody cocktail. Though it would have interesting to note variables like prior vaccination, infecting strain and prior infection and studied their effect on efficacy this study did not do so. However, there were some pre-specified subgroup analysis which yielded pertinent information.

a. Mortality was compared across all age strata -<70 years, 70-79 years and >80 years. Though the point estimate was in the direction of efficacy across all age groups, it was statistically significant and most marked in the 70-79 age group. It was least impressive in the elderly age group of >80 years of age

b. When the overall group was compared to just the seronegative group there was a clear superiority of benefit noted with Casirivimab-Imdevimab in the subgroups < 80 years of age, administered within 7 days of onset and those on just simple oxygen.

While, the recovery trial results indicate that using 4+4 gm of the cocktail in seronegative patients with COVID-19 was significantly associated with reduction in mortality and time to hospital discharge the baseline risk of mortality in the placebo group was much higher  (>30%) than what is seen in Indian patient’s ( 15-20%). Hence the absolute benefits will be lower and number needed to treat will be higher. Hence caution needs to be exercised as such an expensive intervention will need to be justified.  Though data is emerging that this monoclonal antibody cocktail works against the presently circulating variants (B.1.117, B.1.351, B.1.617 etc) it is uncertain that it would continue to maintain its activity against newly emerging variants. In addition, it seems to prudent to use this drug only when the individual is seronegative on a validated antibody test (12) which will be increasingly rare as the pandemic goes on as individuals will either get infected or will be vaccinated. It is possible that with a waning neutralizing antibody response as has been noted with the currently available vaccines in India COVISHIELD and COVAXIN, and possibly a natural infection as well, this drug may assume a role again in specific high-risk category of patients who are at high risk of progression and unable to mount a suitable immune response. Since it is mandatory to have the serostatus of participants before administering the cocktail, centers using this approach would have to have a validated antibody (anti-spike IgG) testing available round the clock (12). It will also become clearer as evidence emerges as to the optimal timing as to when this drug may be delivered in the natural evolution of COVID-19 infection in a patient requiring oxygen.

However, it is a safe drug as has been observed in trials thus far with very rare infusion reactions and no drug interactions or modification required with renal or hepatic impairment.

Monitoring the continued use of this drug is imperative as it will provide valuable information regarding efficacy and utility of the drug with rising seroprevalence and emerging variants. It will also be important to determine whether the immunocompromised, elderly, high risk group of adults, pregnant women and children in the severe to critical category may have a greater benefit with this drug if they have a poor immune response to vaccination or natural infection. We will continue to monitor the relevance of this therapeutic intervention as new evidence emerges for updating this recommendation.

Several interventions like steroids and IL-6 inhibitors have been shown to decrease mortality in moderate, severe and critical categories of COVID-19 infections. Casirivimab Imdevimab is efficacious in early illness and likely functions as an antiviral drug. Hence research priorities would include

1.  Optimal timing of Casirivimab-Imdevimab administration in those with systemic inflammation in severe to critical COVID-19 illness

2.  Identification of the high risk population that is likely to benefit with early administration of Casirivimab Imdevimab.

3.  Analyse if Casirivimab Imdevimab combination is cost effective in severe to critical COVID-19 infection.

4.  Casirivimab Imdevimab efficacy in new emerging variants causing severe to critical COVID-19 infection.

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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-imdevimab-moderate-to-severe/?preview=true  (accessed ).