The first question to ask is that, in a post-vaccination scenario, why is the existence of treatments for COVID-19 important? Juan González, head of the Emergency Unit at the San Carlos Clinical Hospital in Madrid and coordinator of the ERICO project, recalls that there are still a number of patients who can progress, despite being vaccinated, such as the immunosuppressed, the elderly or those with comorbidities. “In this context, we are offered a highly effective treatment such as monoclonal antibodies, which can prevent them from being admitted to the hospital, the ICU, and even from dying. They are essential for the health of the population.”
“From December until now, 800 patients with coronavirus have passed through my hospital – which is a central hospital. In a severe flu we could have 200 patients admitted. Fortunately and thanks to vaccines, mortality has improved a lot, but it is still a problem that should not be forgotten. But you have to put other elements on the table. And the need for hospitalization in a health system at the limit requires strategies to prevent it,” says Álex Soriano, head of the Infectious Diseases Service at the Hospital Clínic de Barcelona.
For González, this reduction in hospitalization not only benefits patients with COVID-19 “but it will benefit the functioning of health in other key aspects, such as the surgical and diagnostic waiting list.”
The objective, for Pablo Guisado, a specialist in Internal Medicine at the Quirónsalud University Hospital in Madrid, should be both to reduce the number of admissions and the duration of hospitalizations after the administration of monoclonal antibodies. “We see a very high vaccination rate in Spain, but in this last wave we have seen the hospitalization of patients not yet vaccinated, which is a target population for the use of these drugs.”
Juan Berenguer, a doctor at the Infectious Diseases and Microbiology Service at the Gregorio Marañón University Hospital in Madrid and coordinator of the ERICO project, agrees that vaccines “are a fantastic tool to combat COVID-19, but they are not a panacea. For this reason, monoclonal antibodies are a complementary tool”.
important step
Rosario Menéndez Villanueva, clinical head of the Pulmonology Service at the Hospital Universitario y Politécnico La Fe de Valencia and coordinator of the ERICO project, points out that the advances that have occurred in these two years would have required “a decade of research because now we have tools, such as monoclonal antibodies, which were not previously used in infections. They allow to avoid or neutralize the microorganism before it progresses and, even, before they develop the infection. It is a very important and innovative step forward, the challenge is to incorporate them into the situation we are experiencing”.
Monoclonal antibodies, explains Berenguer, have a direct and specific mechanism of action, neutralizing the virus and preventing it from binding to the cell receptor. “It would work as an antiviral, but because it is shaped like a pitchfork, because it is attached to the virus or to the cell that has the receptor, it can also stimulate immunity, either with an opsonization decoy mechanism, or by stimulating phagocytosis and cytotoxicity of the infected cells”, he describes.
Regarding efficacy and safety, González emphasizes that in reference studies, monoclonal antibodies have shown high efficacy, reducing the need for hospitalization and death by 80%. Adverse effects “are very rare, the most common is usually diarrhea and occurs in a percentage as low as 2% of patients.” Guisado has added that, in 1%, an infusion reaction can occur, so it is necessary to observe the patients one hour after administration. “None is serious and can be controlled with the medications we use regularly. On the other hand, there are no clearly described pharmacological interactions, which gives great relevance to this therapeutic group”.
Another striking aspect pointed out by Berenguer “and that is not seen in all clinical trials, is that more adverse events were recorded in patients in the placebo arm than in those in the monoclonal antibody arm.”
The profile of the candidate patient is the transplant recipient -or who is receiving immunosuppression or biological treatments because they are people who do not produce their own antibodies-, the elderly and with different comorbidities. Rosario Menéndez underlines that the main ones are chronic kidney failure, diabetes, heart disease, patients with COPD and groups of specific diseases such as cystic fibrosis or people with Down’s disease, in which it has been shown that there is a greater possibility of developing hospitalizations and progression.
In the right moment
“In general, they can be administered to people who weigh more than 40 kilograms and older than 12 years. The patients who benefit the most are those who have less antibody capacity or are more seronegative. And, on the other hand, it is important to use monoclonal antibodies at the right time: during the viral replication phase and, fundamentally, in the first five days from the onset of symptoms”, summarizes Menéndez.
Another indication that has been used, adds Guisado, is hospitalized seronegative patients, with a median of nine days of symptoms, with a mortality benefit in the 28-day follow-up. In his opinion, another important aspect is that serology should be incorporated into hospital care “because it will open the window of options for incorporating this drug, which is probably compatible with the rest of the immunomodulatory treatment we use.”
Are all monoclonal antibodies effective against the omicron variant? Berenguer emphasizes that the available data “are in vitro and they say no. Depending on the drug’s binding area with the virus, there are mutations that affect its sensitivity: not all monoclonal antibodies work on all viral variants. Specifically, in the omicron variant, only one of those currently approved has in vitro action. We must not lose sight of the fact that all the information from the clinical trials comes from the end of 2020 and 2021, when the penetration of the vaccines was very low, with different variants and with groups of patients in which we now see that there is a need and that they were then underrepresented. We still need information from clinical trials with large sample sizes.”
multidisciplinary approach
In this context, ERICO has been launched, a multidisciplinary project, with emergency physicians, internists, infectologists, pulmonologists, intensivists and other specialties. As González summarizes, “we have tried to bring them all together to prepare a document to value the use of monoclonal antibodies, determine which patients benefit from them and insist that there be an adequate structure on the part of the Administration so that these treatments reach patients, with equitable use regardless of the hospital or autonomous community in which they are located”.
The recommendations of the document, as reviewed by Berenguer, “address planning, the need to raise awareness and train Primary Care and specialized professionals and define the most appropriate circuits for use in a health system as specific as ours. And there is a call to collect standardized information in real life”.
Ensuring fairness
One of the main challenges is how to ensure equity and access for high-risk populations. “Monoclonal antibodies are administered by catheter, which requires a certain infrastructure and organization. In some groups, such as those with severe immunosuppression, it is easier because they have closer contact with the hospital. But, being positive, clean circuits must be created so that they do not infect other patients. On the other hand, many of these drugs are accessed for an emergency situation. I hope that this procedure, which has not been easy, will be accelerated and improved,” admits Soriano.
Educational programs are essential for González, so that all doctors who see patients know which are the candidates to be treated and guarantee that those who are high risk receive them.
“In other countries such as Australia, the United States, France or the United Kingdom, monoclonal antibodies are being used more. In Spain and in other countries, we have accepted vaccination as a strategy to combat the pandemic. But the Administration, from the system itself, has not taken into account the role of these drugs as a therapeutic tool to reduce infections, progression, hospital admissions and mortality”, emphasizes Berenguer, who requests the availability of cost-effectiveness studies.
“These drugs present challenges to the system in terms of access, clinical recommendations and certain limitations,” says Guisado, who believes that, after two years of the pandemic, “there should be mechanisms to speed up the availability of drugs, so that they reach patients sooner.” ”. Soriano claims, finally, that these drugs were financed in the aforementioned indications “because their cost is not small.”
“This therapeutic group is here to stay, it is one more option and can coexist with other types of antivirals that use different mechanisms because the patient profile is a little different. And, in addition, it is compatible with immunomodulation therapy, which gives a lot of flexibility in the clinical approach”, concludes Guisado.