As the COVID-19 pandemic enters into its 18-month mark, the global race for novel therapeutics blazes on, with international guidelines being updated to include new therapeutic agents by the flurried month.
Relative to other countries, the face of the pandemic locally has had less worrisome features in Singapore. Today, local data reports 2,014 active COVID-19 cases, with 548 hospitalized and only 7 patients requiring care in intensive care units. These numbers suggest overall that the vast majority of infections are mild. To date, the pandemic has claimed 42 lives locally out of a total of more than 65,000 reported cases, bringing our mortality rate to just 0.1%.
As preparations are now underway to live with COVID-19 as an endemic disease, the focus is turning to the prevention of mortality and severe disease through vaccinations and novel therapeutic agents respectively. This article introduces one such novel therapeutic and its use in Singapore – sotrovimab.
SOTROVIMAB – THE NEW KID ON THE BLOCK
The Health Sciences Authority (HSA) granted interim authorization under the Pandemic Special Access Route (PSAR) for sotrovimab, a monoclonal antibody by GlaxoSmithKline Pte Ltd (GSK) and Vir Biotechnology on 30 June 2021.
Sotrovimab is SARS-CoV-2 monoclonal antibody, designed to attach to the spike protein of the culprit SARS-CoV-2 virus. It inhibits an undefined step that occurs after virus attachment and prior to fusion of the viral and cell membranes. In vitro, sotrovimab exhibited antibody-dependent cell-mediated cytotoxicity (ADCC) in cell culture using isolated human natural killer (NK) cells following engagement with target cells expressing spike protein. Sotrovimab also elicited antibody dependent cellular phagocytosis (ADCP) in cell-based assays using CD14+ monocytes targeting cells expressing spike protein.
A drug cocktail consisting of another two SARS-CoV-2 monoclonal antibodies – casirivimab and imdevimab (marketed as REGEN-COV in overseas markets) is still pending HSA authorization at the time of this report.
Recommendations for administration
Unlike remdesivir, the preceding agent granted conditional approval from HSA for treatment of COVID-19 patients who require oxygen supplementation and breathing support, sotrovimab is intended for the treatment of mild to moderate COVID-19. Specifically, the intended population for sotrovimab includes patients above the age of 18 who do not require oxygen supplementation but are at risk of progression to severe COVID-19.
Risk factors for progression to severe disease as defined by HSA include:
- being aged above 55
- and/or with comorbidities such as chronic kidney disease, chronic obstructive pulmonary disease, congestive heart failure, diabetes, moderate to severe asthma, and obesity.
Sotrovimab is recommended to be administered as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset in patients who fit the risk profile for progressing to severe COVID-19. It is administered as a single intravenous (IV) infusion of 500mg.
Dose adjustments and contraindications
There are no dosage adjustments recommended in renal impairment and the drug has not been studied in patients with hepatic impairment. There is also presently no data available for the use of sotrovimab in patients below the age of 12 or with a body weight less than 40 kilograms. To date, no contraindications for sotrovimab have been published.
SOTROVIMAB – SO FAR SO GOOD?
The prevailing evidence for sotrovimab hails from the interim results of the phase 3 COMET-ICE trial – a multi-center, double-blind, placebo-controlled study. The ongoing trial evaluated the safety and efficacy of sotrovimab in non-hospitalized participants against placebo.
In a nutshell, the interim analysis from 868 patients (of which 430 received the treatment drug and 438 received placebo) demonstrated an 85% reduction in hospitalization for more than 24 hours or death, favouring treatment with sotrovimab. The results for this primary efficacy endpoint was found to be statistically significant (p=0.002).
All subjects were enrolled within 5 days of symptom onset and did not require oxygen supplementation at baseline. Safety data released thus far also suggests that the drug is well tolerated – adverse events reported were all mild to moderate (Grade 1 or 2), with the most common being rash and diarrhea in low incidences.
While the interim study results appear promising, it should be highlighted that clinical worsening of COVID-19 has been reported after administration of SARS-CoV-2 monoclonal antibody treatment, although it remains unclear if these adverse outcomes were directly caused by administration of the drug or clinical progression of the disease. The complexities of interpreting the trial results are inherent to the context of the drug being used to prevent the development of severe disease based on a broad risk profile.
Sotrovimab and its practice overseas
Beyond our shores, while the United States Food and Drug Administration (FDA) has also granted Emergency Use Authorization (EUA) to sotrovimab, this authorization is restricted to outpatients and does not extend to patients who are hospitalized for COVID-19 or require oxygen therapy due to COVID-19. Instead, it makes a concession that patients who have been hospitalized for reasons besides COVID-19 but who report mild to moderate symptoms of infection (confirmed with viral testing) and are at risk of developing severe disease may be considered for sotrovimab treatment.
In contrast, the HSA’s authorization is less prescriptive about the setting of where the drug is used, as long as the patient profile matches the listed risk factors. To our best understanding, the drug is currently only being administered in the inpatient setting locally due to its route of administration.
SO HOW?
In summary, there is much that remains to be understood of the true efficacy and safety of the novel SARS-CoV-2 monoclonal antibody sotrovimab. Given the likelihood that such therapeutics while available and accessible are likely to be costly, the cost effectiveness of this treatment will require an in-depth health technology assessment to determine its utility in our local population. This is especially as COVID-19 gears toward endemnicity, and the increasing majority of the population is vaccinated and expected not to develop severe disease even if infected.
Till then, or at least until results of the ongoing COMET-ICE study are published in full, the use of sotrovimab remains nebulous and largely dependent on clinicians’ judgement and patient agency.
Additional Resources:
- https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Sotrovimab/pdf/SOTROVIMAB-EUA.PDF#nameddest=HCPFS
- https://reference.medscape.com/drug/sotrovimab-4000220
- https://www.hsa.gov.sg/announcements/news/hsa-sotrovimab
- https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx
- https://www.fda.gov/media/149534/download
