FasL Inhibitor Asunercept Speeds COVID-19 Recovery

A new clinical trial demonstrates that an inhibitor of Fas ligand (FasL), also known as CD95 ligand (CD95L), leads to a faster recovery of COVID-19 patients and lower mortality. Patients treated with asunercept, a biotherapeutic FasL inhibitor, recovered in an average of eight days, compared to 13 days in the control group. In addition, mortality was reduced by around 20%. The article ‘Efficacy and safety of asunercept, a CD95L-selective inhibitor, in hospitalized patients with moderate-to-severe COVID-19: ASUNCTIS, a multicenter, randomised, open-label, controlled, phase 2 trial’ was published in eClinicalMedicine.

FasL’s physiological duty is to keep immune system cells, known as T lymphocytes (short T cells), under control by killing them once they have completed their activity. However, in patients with severe COVID-19, the immune system becomes hyper-activated, resulting in an excess of FasL production. As a result, FasL performs two functions: it kills far too many T cells while simultaneously attacking normal lung cells. This abnormal increase in cell death causes lymphopenia, or the loss of lymphocytes, as well as significant lung inflammation, both of which are hallmarks of severe COVID-19. The new therapy strategy is based on suppressing FasL, which prevents the unintended death of T cells and lung epithelial cells, as well as the associated inflammation.

Academic members of the clinical trial research team recently demonstrated in a preclinical model that therapeutic FasL inhibition greatly enhanced survival of mice with severe COVID-19. The phase II dose-finding study with the FasL inhibitor asunercept was initiated as an academic-industrial collaboration by Professor Henning Walczak and his team at the University of Cologne and University College London (UCL), as well as Professor Michael Bergmann at the Medical University of Vienna and Dr. Thomas Hoeger at Apogenix GmbH, a biotech company based in Heidelberg. From October 2020 to December 2021, the clinical trial was carried out at eleven study centers in Spain and Russia.

It is important that the inhibition of FasL targets the overreaction of the host’s immune system rather than the virus itself. I am therefore confident that our approach should be effective not only during future outbreaks of SARS-CoV-2 variants of concern, but possibly also for other respiratory RNA viruses that may emerge in the human population in the future. Especially before vaccines against such viruses become available, it would be crucial to have such drugs at our disposal from the very beginning should another pandemic situation arise.”

Henning Walczak, Alexander von Humboldt Professor of Biochemistry at the Faculty of Medicine and the CECAD Cluster of Excellence for Aging Research at the University of Cologne and Professor of Tumour Biology at the UCL Cancer Institute

The study included 438 patients and was led by Dr. Maria Pilar Ruiz Seco (Infanta Sofía University Hospital, Madrid), Dr. Jose Ramon Paño Pardo (University of Zaragoza/IIS Aragón/CIBERINFEC), and Dr. Christian Schörgenhofer (Medical University of Vienna). Professor Bernd Jilma, Deputy Head of Clinical Pharmacology at Medical University of Vienna, supervised the study. Participants were separated into four groups. All patients were given standard of care treatment. In addition, three of the four groups received varying dosages of the FasL inhibitor asunercept (25 milligrams, 100 milligrams, and 400 milligrams per week) and were compared to the control.

The 100 and 400 mg doses exhibited the best tendency for early recovery after an average of eight days, while the 25 mg dose took nine days. Patients in the standard-of-care control group showed clinical improvement after an average of 13 days. While statistical significance was narrowly missed in each of the individual dose groups, a post-hoc analysis combining the three asunercept dose groups revealed a significant therapeutic effect of the FasL inhibitor, with an average recovery time of eight days versus 13 days in the control group. The 100 and 400 mg doses were also found to reduce mortality by about 20%. Overall, this trial demonstrated that the FasL inhibitor was safe and well tolerated by patients, with extremely encouraging results for its efficacy in patients with severe COVID-19.

These results render the inhibition of FasL among the few concepts identified during the COVID-19 pandemic as potentially therapeutically valuable. “Even though further clinical trials are required to confirm the efficacy, our study shows that the administration of the FasL inhibitor has a positive effect on patients. In future pandemics, the shorter recovery time could reduce the burden on the healthcare system on the one hand and the restrictions for the population on the other,” said Michael Bergmann, surgeon and researcher at the Medical University of Vienna. In addition, increased levels of FasL are also found in samples from the lower respiratory tract of patients who are severely ill following infection with a pandemic version of the influenza A virus, which could extend the field of application in the future.

For more information: Pilar, M., et al. (2024). Efficacy and safety of asunercept, a CD95L-selective inhibitor, in hospitalised patients with moderate-to-severe COVID-19: ASUNCTIS, a multicentre, randomised, open-label, controlled, phase 2 trial. eClinicalMedicine. doi.org/10.1016/j.eclinm.2024.102879.