Hot on the heels of sotrovimab, the Health Science’s Authority (HSA) has granted pandemic special access route (PSAR) interim authorization to another monoclonal antibody therapeutic for the treatment of mild to moderate COVID-19 – casirivimab and imdevimab , coformulated and marketed as REGEN-COV. The drug cocktail is developed by Regeneron and Roche.
In the past month, COVID-19 has seen a resurgence in the local population, despite it having achieved target vaccination rates. At the time of this writing, 1288 COVID-19 cases were warded in local hospitals in Singapore. Statistics over the preceding 28 days of this report revealed that of infected individuals, 98% of patients had mild symptoms or were asymptomatic, with just 1.7% requiring oxygen supplementation. The overall mortality rate of COVID-19 in Singapore is just 0.1%.
On closer examination of the profile of COVID-19 fatalities, the majority of the 80 fatalities were elderly individuals who were either unvaccinated or who had multiple comorbidities.
Present statistics suggest an urgent need to identify and have accessible treatment for groups at highest risk of mortality from COVID-19.
How does it work?
REGEN-COV consists of two individual, non-competing fully human immunoglobulin G1 monoclonal antibodies. They bind to non-overlapping epitopes on the receptor binding domain of the spike protein of SARS-CoV-2 and neutralises the virus.
Recommendations for use
The HSA’s PSAR authorizes adult patients aged ≥ 18 years with COVID-19 who do not require oxygen supplementation and who are at risk of progressing to severe COVID-19.
Individuals who are at risk are identified as:
- those aged above 50 years, and / or having comorbidities such as:
- chronic kidney disease (including those on dialysis)
- chronic lung disease (including asthma)
- cardiovascular disease (including hypertension)
- chronic metabolic disease (including diabetes)
- chronic liver disease
- immunosuppression
- obesity (BMI >30 kg/m2).
The PSAR currently restricts the prescription of casirivimab/imdevimab to Infectious Disease physicians.
Locally in Singapore, the National Centre for Infectious Disease (NCID) remains the authoritative voice on COVID-19 management in the country. The latest iteration of their guidelines, published 28 July 2021, recommends that casirivimab plus imdevimab may be considered for:
- Carefully selected patients with mild to moderate illness who are not on oxygen, but are at high risk of disease progression.
- Patients with severe COVID-19, who are seronegative.
The guidance further recommends that treatment should be initiated within 10 days of symptom onset, and that priority should be given to those who are unvaccinated for COVID-19, or are seronegative for SARS-CoV-2.
Clinicians should be cognizant that monoclonal antibodies may be associated with worse clinical outcomes when administered to hospitalised patients with COVID-19 requiring high flow oxygen or mechanical ventilation, although this may be due to progression of disease.
It should also be noted that the place in therapy of casirivimab plus imdevimab for vaccinated individuals is currently unknown, given that studies found benefit in patients who have yet to mount their own immune response, and there has yet to be data on the use of the drug cocktail in the vaccinated population.
Administration
REGEN-COV is administered as a dose of 600mg casirivimab and 600mg of imdevimab by intravenous (IV) infusion over 20-30 minutes, diluted with 50 -250ml of Normal Saline (NS).
There are currently single-dose vials containing a co-formulated solution of both drugs, as well vials of individual agents that must be combined prior to administration available in the market. According to the HSA, the product available locally is a co-package of individual vials of 120mg/ml casirivimab and imdevimab concentrate solution.
While not mentioned in the HSA PSAR, the subcutaneous route of administration for casirivimab plus imdevimab has been studied in symptomatic COVID-19 patients. The study found both subcutaneous and IV routes of administration to yield similar viral load lowering efficacy, thereby offering an alternative for patients who are unable to receive the drug intravenously albeit based on limited data.
Efficacy data
The evidence base for the use of casirivimab plus imdevimab is from pre-planned interim analyses of phase 3 data from R10933-10987-COV-2067, an ongoing Phase 1 to 3, randomised, double blind, placebo-controlled trial in outpatients with mild-moderate COVID-19.
R10933-10987-COV-2067 Phase I/II results
Phase I and II of the study compared a single IV infusion of 2.4g of casirivimab and imdevimab (1.2g of each mAb) vs 8g of casirivimab and imdevimab (4g of each mAb) vs placebo in addition to standard of care. Results concluded that:
- Carisivimab and imdevimab reduced viral load, with a positive trend towards reduction in medical visits
- Benefits were found to be greatest in individuals who had high viral load (-0.78 log10 copies/mL) or who had not mounted their own effective immune response
- There was no significant difference between virologic or clinical efficacy between the 2 dosage regimens
R10933-10987-COV-2067 Phase III results
Phase III of the study then examined a single IV infusion of 1.2g of casirivimab and imdevimab (600mg of each mAb) vs 2.4g of casirivimab and imdevimab (1.2g of each mAb) vs placebo.
- Primary endpoint: Proportion of patients with ≥ 1 COVID-19 related hospitalization or all cause death through day 29.
- Results:
- 600mg casirivimab and imdevimab resulted in 70% relative reduction in hospitalisation and all cause death as compared to placebo.
- Comparable results (71% relative reduction) for 1.2g casirivimab and imdevimab as compared to placebo.
- The secondary endpoint of median time to symptom resolution was also achieved (10 days for casirivimab plus imdevimab vs 14 days for placebo for both dosage regimens)
In the Phase III study, treatment was initiated within 3 days of positive PCR results.
Another study, the RECOVERY trial, compared casirivimab and imdevimab arm (single IV infusion of 4g of each) with usual care vs usual care alone
- Usual care included remdesivir in 25% of patients and tocilizumab in 14% of patients
- Preliminary data analyses of trial results, while not peer reviewed, indicated that casirivimab plus imdevimab can reduce mortality in patients hospitalised with COVID-19 who have not mounted a natural antibody response.
The results of this study are the basis for the conditional recommendation in the NCID guidelines that suggest a higher 8g dose may be considered for seronegative (antispike IgG negative or neutralizing antibody, e.g. Cpass negative) patients with severe COVID-19, albeit on a case-by-case basis.
Casirivimab plus imdevimab as post exposure prophylaxis
Beyond our shores, casirivimab plus imdevimab has been granted emergency use authorization (EUA) by the United States Food and Drug Administration (FDA) for post exposure prophylaxis (PEP), in addition to treatment for mild to moderate COVID-19 at risk for progression to severe disease. It is recommended in the National Health Institute (NIH) guidelines for individuals who are at high risk of acquiring SARS-CoV-2 infection and are at high risk of progressing to serious illness if infected.
Safety data
The main adverse effects reported in the trials are infusion-related or injection site reactions.
Infusion-related reactions of grade 2 (moderate; minimal, local or non-invasive intervention indicated) or higher severity were observed in 0.2% of trial participants, and included anaphylaxis, fever, arrhythmia, angioedema, rash, pruritis, vasovagal reactions and bronchospasm among others.
Utility of carisivimab plus imdevimab in Singapore’s context
Given that Singapore has now achieved a national vaccination rate of more than 80%, it remains unclear if the therapeutic will be of benefit to its recipients if used off label due to the lack of data. The cost of the drug, if born by the patients, should be taken into consideration in light of this and therapy should be an informed decision made in collaboration between clinicians and their patients.
