A new therapeutic approach targeting the host's immune response in severe COVID-19 has shown promising results in a Phase 2 clinical trial. The study, conducted by an international research consortium, found that inhibiting Fas ligand (FasL) with asunercept led to faster recovery and reduced mortality in hospitalized patients with moderate-to-severe COVID-19.
The study, published in eClinicalMedicine, demonstrated that patients receiving asunercept, a biotherapeutic FasL inhibitor, recovered in an average of eight days, compared to 13 days in the control group. Furthermore, mortality was reduced by approximately 20% in patients treated with the 100mg and 400mg doses.
Understanding FasL and its Role in COVID-19
FasL, also known as CD95 ligand (CD95L), plays a crucial role in regulating the immune system by inducing apoptosis (programmed cell death) in T lymphocytes once they have fulfilled their function. However, in severe COVID-19, the immune system becomes hyper-activated, leading to an overproduction of FasL. This overproduction results in the excessive death of T cells and the attack of normal lung cells, contributing to lymphopenia and severe lung inflammation, both hallmarks of severe COVID-19.
The therapeutic concept behind asunercept is to block FasL, thereby preventing the excessive death of T cells and lung epithelial cells, and reducing the resulting inflammation.
Clinical Trial Details and Results
The Phase 2 dose-finding study was an academic-industrial collaboration involving researchers from the University of Cologne, University College London (UCL), the Medical University of Vienna, and Apogenix GmbH. The trial was conducted at ten study centers in Spain and Russia between October 2020 and December 2021, involving 438 patients.
Participants were divided into four groups, all receiving standard of care treatment. Three of the groups also received different doses of asunercept (25 mg, 100 mg, and 400 mg per week), which were compared to the control group. The 100 mg and 400 mg doses showed the most beneficial tendency for early recovery, with an average of eight days, while the 25 mg dose showed recovery after nine days. Patients in the standard-of-care control group achieved clinical improvement after an average of 13 days. Although statistical significance was narrowly missed in each of the individual dose groups, a post-hoc analysis combining the three asunercept dose groups showed a significant therapeutic effect (p<0.05) of the FasL inhibitor in terms of an earlier recovery of eight days on average instead of 13 days in the control group. The 100 mg and 400 mg doses were also associated with a reduction in mortality of approximately 20%.
Implications and Future Directions
Professor Henning Walczak from the University of Cologne and UCL emphasized the importance of targeting the host's immune overreaction 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," he stated.
Dr. Michael Bergmann from the Medical University of Vienna added that the shorter recovery time could reduce the burden on the healthcare system and the restrictions for the population during future pandemics. He also noted that increased levels of FasL are found in samples from the lower respiratory tract of patients severely ill with pandemic influenza A virus, suggesting a broader potential application for FasL inhibition.
While further clinical trials are required to confirm the efficacy of asunercept, the current study indicates that FasL inhibition is a promising therapeutic strategy for managing severe COVID-19 and potentially other severe respiratory viral infections.
