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An international study, with the participation of the University of Zaragoza and the Aragon Health Research Institute (IIS Aragón), has tested a new therapeutic strategy to treat severe COVID. It is a clinical trial whose results are published in eClinicalMedicine and that could also have application in other respiratory viruses
A new clinical study, with the participation of Julián Pardo, Diego de Miguel and José Ramón Paño Pardo at the University of Zaragoza and the Aragón Health Research Institute (IIS Aragón) and Mª Pilar Ruiz Seco from the Infanta Sofía University Hospital, has tested A new therapeutic concept to treat virus-induced lung failure in patients with severe COVID-19The study, a multicenter, randomized, open-label, controlled phase 2 trial, has been published in eClinicalMedicine.
Specifically, the work shows that an inhibitor of the Fas ligand (FasL), a molecule involved in the regulation of cell death and immune homeostasis, accelerated the recovery of COVID-19 patients and reduced mortalityOn average, patients receiving Asunercept, a biopharmaceutical inhibitor of FasL, recovered in eight days, compared with 13 days in the control group. In addition, mortality decreased by about 20 percent.
Reducing lymphocyte loss and severe lung inflammation, two characteristics of severe COVID-19
“The physiological role of FasL is to keep immune system cells, T lymphocytes, under control, eliminating them when they have fulfilled their function. However, in patients with severe COVID-19, the immune system becomes hyperactive, causing an overproduction of FasL” explains Julián Pardo, who is also a researcher in the area of infectious diseases at CIBER (CIBERINFEC). “As a result - he adds - FasL eliminates too many T lymphocytes and also attacks normal lung cells. This abnormal increase in cell death causes lymphopenia (loss of lymphocytes) and severe lung inflammation, two key features of severe COVID-19.” Thus, The new therapeutic concept is based on blocking FasL to prevent excessive death of T cells and pulmonary epithelial cells and thus reduce the associated inflammation.
Previously, the international team had shown that therapeutic inhibition of FasL significantly increased the survival of mice with severe COVID-19. This new phase II dose-finding trial with the FasL inhibitor asunercept was initiated as an industry-academia collaboration by the University of Cologne and University College London, as well as the Medical University of Vienna and Apogenix GmbH, a biotechnology company from Heidelberg, Germany, in collaboration with Julián Pardo and Diego de Miguel (IIS Aragón). The clinical trial was conducted at ten study centers in Spain and Russia between October 2020 and December 2021.
The authors argue that “it is important that FasL inhibition is directed at the overreaction of the host immune system rather than the virus itself” and are confident that that the approach may be effective not only in future outbreaks of SARS-CoV-2 variants of concern, but also for other respiratory RNA viruses that may emerge in the human population in the future“Especially before vaccines against these viruses are available, it would be crucial to have such drugs available early if another pandemic situation occurs,” explains Henning Walczak, Alexander von Humboldt Professor of Biochemistry at the Faculty of Medicine and the CECAD Cluster of Excellence for Ageing Research at the University of Cologne and Professor of Tumor Biology at the Cancer Institute of University College London.
A shorter recovery time that could reduce the burden on the health system
A total of 438 patients participated in the study, led by María Pilar Ruiz Seco (Infanta Sofía University Hospital, Madrid), José Ramón Paño Pardo (University of Zaragoza/IIS Aragón/CIBERINFEC) and Christian Schörgenhofer (Medical University of Vienna), under the supervision of the head of Clinical Pharmacology at the Medical University of Vienna, Professor Bernd Jilma. All participants, divided into four groups, received conventional treatments plus different doses of the FasL inhibitor asunercept (25, 100 and 400 milligrams/week) compared with the control group.
“The 25- and 400-mg doses showed greater benefit in early recovery after an average of eight days, and the 25-mg dose after nine days; patients in the standard-care control group achieved clinical improvement after an average of 13 days,” the authors explain. Although statistical significance was not reached in each of the individual dose groups, a subsequent analysis combining the three dose groups showed a significant therapeutic effect of the FasL inhibitor in terms of earlier recovery, with an average of eight days instead of 13 days in the control group.
Doses of 100 and 400 mg were also associated with a reduction in mortality of approximately 20%. Overall, this study showed that the FasL inhibitor was safe and well tolerated by patients, and that it provided very promising results regarding the efficacy of this drug in patients with severe COVID-19.
These results place FasL inhibition among the few concepts identified during the COVID-19 pandemic as potentially valuable in the therapeutic field. “Although further clinical trials are required to confirm efficacy, our study shows that administration of the FasL inhibitor has a positive effect on patients. In future pandemics, the shorter recovery time could reduce the burden on the health system on the one hand and restrictions for the population on the other,” notes the Zaragoza team. In addition, elevated levels of FasL are found in samples from the lower respiratory tract of severely ill patients after infection with a pandemic version of the influenza A virus, which could extend the field of application in the future.
Source: Press release University of Cologne / University of Zaragoza / CIBERISCIII
