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The World Health Organisation (WHO) has updated its clinical care guidance to include the drugs casirivimab and imdevimab (produced by Regeneron) for treatment of non-severe COVID-19 patients who are at highest risk of hospitalisation, as published in the BMJ.
Dr Kovilen Sawmynaden, Principal Scientist, LifeArc, said:
“This is useful guidance as it highlights clearly where these antibodies are likely to have the most benefit and it is good news that this medicine is now available on the NHS.
“The guidance summarises the relevant clinical trials (and cites them). In particular, the RECOVERY trial which showed the beneift of using antibodies in hospitilised patients (without any exisiting antibodies) for the first time.
“Monoclonal antibodies are important tools in the fight against COVID-19. They are complementary to (not a replacement for) our current and highly effective vaccine approach here in the UK.
“Casirivimab and Imdevimab (Ronapreve) work together to prevent the virus (SARS-CoV2) from infecting cells lining the respiratory tract and has recently shown efficacy in two broad patient groups: high-risk patients (unvaccinated, immunocompromised and older people) and hospitalised patients whom importantly have no detectable antibodies themselves (i.e. are seronegative).
“Importantly, this drug is not suitable for treating severe or chronic disease in hospitatilised patients, whom already have detectable antibodies. It showed no efficacy in this group, during clinical trials. In fact, there may be a risk that using an anti-viral antibody at this point could be detrimental to patient progression, especially if it functions to potentiate the immune response at a point when you are essentially trying to ‘calm it down’ (e.g. using corticosteroids).
“Both these antibodies are ‘first generation’, that is they were developed before the emergence of new variants of concern (VOC: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). The use of a ‘cocktail’ aims to mitigate any issues arising from this, however it is possible that at least one of these antibodies has reduced effectiveness. How future-proof this medicine is, remains to be seen.
“The required dose is high (1.2 grams) and administration (as with all antibodies) is parenteral (non-oral administration, i.e. needs to be administered by someone else; so, a nurse giving an injection or inserting an IV drip). In practical terms, this medicine will need to be given within a hospital setting and by intravenous injection (IV) which limits its range. Cost of manufacturing and lead times may affect general availability.”
Dr Ed Moran, Consultant in Infection and Clinical Lead for Infectious Disease, Southmead Hospital, said:
“The WHO recommendation for the use of novel monoclonal therapy, casirivimab-imdevimab, for the treatment of certain patients with coronavirus is timely and welcome.
“Researchers and clinicians have risen to the challenge presented by coronavirus and evidence for and against various treatments has accumulated at an impressive rate. The “living guideline” approach taken by the WHO has allowed experts to sift this evidence and rapidly promote those therapies most likely to be effective, and warn against those that are not. This antibody treatment – already used in the USA and EU and shortly to be deployed in the UK – is an important addition and one clinicians have been waiting for. The guideline authors pooled data from four high quality trials and found that the treatment was likely to reduce the number of those with non-severe illness progressing to the point where they required admission to hospital. In addition they looked at data from the large UK-based RECOVERY trial – an important study that has produced key data informing treatment recommendations throughout the pandemic – and agreed that casirivimab-imdevimab should be given to those with severe infection if they showed no evidence of an immune response to coronavirus as indicated by an antibody test.
“However it is important to remember that whilst exciting, the treatments recommended by the WHO – with the exception of steroids – remain out of reach of the majority of the world’s population, for both reasons of expense and practicality. Given this, it is even more important that wealthy countries address the iniquitous distribution of vaccines across the world. Our priority should be reducing the number of people who get sick and whose lives might otherwise have been saved by such treatments.”
Prof Penny Ward, Independent Pharmaceutical Physician, Visiting Professor in Pharmaceutical Medicine at King’s College London, said:
“This living guideline provides a consensus statement based on available evidence from multiple sources on the effectiveness of various interventions for the management of COVID disease. The guideline focuses early comments on the use of the monoclonal antibody combination treatment casirivimab-imdevimab, which is newly added to the guideline. The recommendation for use of this product includes community treatment with a single dose in patients at high risk of severe disease (older adults with other comorbidities/taking immunesuppressing agents) based on evidence from trials in this group demonstrating reduction in hospitalisation rate if given within 4 days of symptom onset. The group acknowledge that administration in a community setting is challenging. In the UK use of home infusion services might be one approach, or an infusion center approach with appropriate PPE protection for staff. In addition, the group recommend use in seronegative hospitalised patients with more severe disease based on data from the RECOVERY trial, which demonstrated reduced mortality from COVID in this subset of hospitalised patients. As this benefit was only observed among patients that had not mounted an immune response, centres would need access to rapid antibody testing which may not be available in some areas of the world. Currently the NHS appears to have focused use of this agent in hospitalised patients, even though a reduction in hospitalisation rates would be very helpful in parts of the UK in which bed demands are already overstretched. Perhaps the availability of this recommendation from an international group may help to change minds and encourage hard pressed regions to introduce wider availability of this treatment for high risk patients. The guideline does not discuss the use of this treatment for the prevention of COVID in contacts of cases, which is an omission, particularly for parts of the world where vaccination rates remain low but is also worth considering to curtail nosocomial (hospital) transmission and reduce outbreaks of disease in institutional care homes, high impact workplaces etc in the UK. Something to consider for further research perhaps.
“The Guideline group have included several statements suggesting potential patient preferences for/against treatments. This seems to have been a Delphi survey exercise among the guideline group rather than among the lay public. They may wish to consider how to better involve the public in this exercise in future as the comments made seem to reflect the recommendations made, rather than considering the potential that patients may have different preferences if offered unbiased information and an open choice whether or not to accept intervention.
“Recommendations for other treatments are unchanged from previous versions. The group have not considered the results of the PRINCIPLE trial, which suggested early use of inhaled steroid might prevent hospitalisations in infected patients when started in the first week of illness. There is no discussion of this in the paper. In addition, the recent press release from Gilead concerning the effectiveness of early outpatient treatment with remdesivir presumably arrived too late to be considered for inclusion. It is hoped that the detailed study data will soon be made available to enable appropriate assessment given the groups recommendation against use of remdesivir in hospitalised patients. Taken together the data from monoclonal antibodies and from early use of remdesivir suggest that effective antiviral treatment early in the course of disease may significantly reduce the burden of illness within most health care systems. An effective oral antiviral would obviously be particularly helpful in this respect. Let us hope that at least one of the products in current clinical trials is effective. With a combination of vaccines and antiviral medications to treat breakthrough disease early, COVID can – and will – be overcome.”
‘RAPID RECOMMENDATIONS: A living WHO guideline on drugs for covid-19’ by Bram Rochwerg et al. was published in the BMJ at 00:01 UK time on Friday 24 September 2021.
DOI: 10.1136/bmj.m3379
Declared interests
Dr Kovilen Sawmynaden: “LifeArc is a medical research charity. We are part of the BIA Antibody Taskforce to identify potential neutralising antibodies for Sars-Cov-2, donating our time and efforts on this project.”
Dr Ed Moran: “No conflicts of interest.”
Prof Penny Ward: “I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”