December 2021 brought great news for European COVID-19 patients, their health care providers, and the whole population suffering from medical and non-medical impacts of the pandemic. Just days before the second anniversary of the first report of the new disease in Wuhan, the EMA’s human medicines committee (CHMP) recommended authorizing three new treatments for COVID-19 patients: Xevudy, Kineret, and RoActemra.

Xevudy (sotrovimab) is the third monoclonal antibody product authorized in the EU for treating COVID-19, following the approval of Regkirona and Ronapreve in November. Monoclonal antibodies are proteins designed to attach to a specific target, in this case, the spike protein of SARS-CoV-2, which the virus uses to enter human cells. All three monoclonal antibody products have been authorized for treatment of patients who have mild symptoms and do not require supplemental oxygen, but who are at risk of increasingly severe disease. 

With regard to patients who progress to severe disease and require supplemental oxygen, Veclury (remdesivir) was until now the only medicine authorized by the EMA and European Commission (since July 2020). Treatment with dexamethasone (corticosteroid) containing products with earlier marketing authorizations in EU member states was endorsed by the EMA in September 2020 for this population and has become a standard of care.

Targeting Immune Response

The two new products approved by the EMA and European Commission in December 2021 for hospitalized patients requiring oxygen are both well-known immunosuppressants authorized earlier for treatment of various inflammatory conditions, targeting the cytokines involved in the immune response. Overreaction of the immune system, hyperinflammation (sometimes called “cytokine storm”), is believed to be part of the pathogenetic mechanism leading to respiratory failure in patients critically ill with COVID-19. Both anakinra (Kineret), targeting interleukin-1, and tocilizumab (RoActemra), targeting interleukin-6, have shown greater clinical symptom improvements and reduced the number of patients with COVID-19 whose condition worsened to respiratory failure or death.

The developments of anakinra and tocilizumab for the COVID-19 indication share several common features and peculiarities.

1.      Both medicines have been used by physicians off label since the first days of the pandemic and have become part of various treatment protocols and recommendations. Tocilizumab has been approved for emergency use by the U.S. FDA.

2.      However, the reports from clinical trials have been inconsistent and even controversial.

3.      Pivotal evidence allowing conclusions on positive benefits for both products came not from studies sponsored by marketing authorization holders, but from studies conducted by academic investigators. The “RECOVERY” study with tocilizumab, sponsored by University of Oxford, and the “SAVE-MORE” study with anakinra, sponsored by Hellenic Institute for the Study of Sepsis, showed significant decrease in mortality and length of hospitalization in a treatment group of patients compared to a group receiving standard care.

Studying Biomarkers to Advance Precision in Treatment

By reviewing results of all clinical trials conducted from the beginning of the pandemic, it has become obvious that biologic anti-cytokine treatment does not help all patients. The question of identification of the subpopulation that would positively respond to this intervention remains crucial for doctors treating COVID-19 patients, as well as for regulators and public health administrators. Among other reasons (notwithstanding the pharmaco-economy), this is because immune suppression in critically ill patients with infectious disease can be counterproductive. The presence of classical risk factors like age, obesity, and diabetes is not sufficient in identifying the susceptible COVID-19 patient population. To help in finding the right moment in the course of the disease when the immune system is getting out of control and needs to be suppressed without unnecessary harm, investigators were looking for the set of laboratory biomarkers of inflammation.

The picture is far from clear yet for defining the values applicable for precision treatment of severely ill COVID-19 patients, but both newly approved medicines made a significant attempt to come closer to solving the mystery. Entry criteria for both trials included increased level of inflammatory biomarkers (C-reactive protein, or “CRP,” for tocilizumab, and soluble urokinase plasminogen receptor, or “suPAR,” for anakinra) for specification of patients likely to respond.

Other biomarkers being studied are ferritin, interleukin-6, D-dimer, and others, with some attempts to define the cut-off value for their combination score. Further research including genetic susceptibility is highly needed. Sadly, after two years of humankind fighting the pandemic, there is no comprehensive clinical consensus on the diagnostic and therapeutic algorithm in management of severely ill COVID-19 patients.

Learning from a Complex Development Process

The complexity of the development led to significant delays in applications for new COVID-19 indications by marketing authorization holders for both products. Controversial results stemmed from several clinical trials that were not optimally designed or that were insufficiently powered. This is despite the fact that Kineret and RoActemra are well-known products with acceptable safety profiles used for years in treatment of autoimmune diseases. Although the evaluation procedures by the EMA CHMP were faster than “usual”, in light of the urgency of the pandemic situation, they were still relatively lengthy due to complexity of the data. This might illustrate the necessity of creating an emergency use authorization tool for timely access in Europe similar to that of the FDA. (The evaluation period for RoActemra was 27 July to 6 December and for Kineret, 19 July to 16 December.)

Still, it is remarkable that after vaccines and monoclonal antibodies for treatment of mild disease have become available, we now have in hand approved medicines for severely ill COVID-19 patients with high mortality risk. This is certainly reason for congratulations and celebration. Discussions of lessons learned from COVID-19 for the next pandemic have started, and critical search for improvement possibilities is warranted.

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