While there’s no cure yet for COVID-19 and supportive therapies have not been effective in treating patients with severe respiratory dysfunction, one drug—Soliris®—has been FDA-approved as a hospital-based emergency treatment at participating U.S. hospitals. Researchers at The Ohio State University College of Medicine are conducting a study of Soliris® to assess its efficacy, safety, long-term effects and survival rates.
“Soliris®, generically known as eculizumab, has been studied extensively in the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, and has proven to be an effective terminal complement inhibitor with a well-established safety profile,” says Sumithira Vasu, MBBS, associate professor of Internal Medicine at Ohio State College of Medicine, a hematologist-oncologist at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and a lead investigator in the study. Spero Cataland, MD, professor of Internal Medicine at Ohio State College of Medicine, was the original researcher who investigated the role of complement pathways in atypical hemolytic uremic syndrome (aHUS) and established a research program evaluating the role of complement inhibition using eculizumab in aHUS. His leadership paved the way for evaluation of the complement pathway in COVID-19.
Dr. Vasu, who also serves as scientific director of the Blood and Marrow Transplantation Program and medical director of the Cell Therapy Lab, Blood and Marrow Transplantation Section, notes that complement inhibition has been shown to be an effective therapeutic target in hematological and neuroinflammatory diseases.
The complement system is a part of the body’s innate immune response that plays an important role in inflammation, host homeostasis and host defense against pathogens, and is the system’s first response to SARS-CoV-2 infection. Unrestrained activation of the complement system, known as a “cytokine storm,” is induced by the virus in the lungs and other organs and plays a major role in acute and chronic inflammation, endothelial cell dysfunction, thrombus formation and intravascular coagulation, ultimately contributing to multiple organ failure and death.
Inhibiting the complement alternative pathway would appear to prevent the advance of SARS-CoV-2, but studies using mouse models suggest that inhibition of the complement alternative pathway alone is not enough, leading researchers to target a key relay point, such as complement component 5 (C5) or complement component 3 (C3), the proteins that are encoded in humans by the C3 and C5 genes.
“Soliris® produces complete and sustained inhibition of C5-mediated terminal complement activity, and has been used to modulate the activity of the distal complement, preventing the formation of the membrane attack complex,” says Dr. Vasu. “By modulating this portion of the immune response, mortality can be halted while the patient has time to recover from the virus with supportive medical care.”
Previous research has shown that the C3c fragment is present in the sera of patients with SARS and is a strong indicator of disease severity (Pang 2006). Consistent with this, the complement activation product C5a is associated with the inflammatory response and severe lung damage that occurs in patients infected with the 2009 H1N1 influenza virus (Ohta 2011). It has also been shown that SARS-CoV can directly activate complement via the lectin pathway (Ip 2005). Patients with SARS develop autoantibodies against human epithelial cells and endothelial cells that mediate complement-dependent cytotoxicity (Yang 2005).
“Soliris® is a monoclonal antibody that specifically binds to C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9,” says Dr. Vasu. “Inhibiting C5 cleavage effectively blocks the generation of the potent pro-inflammatory molecule C5a and the cell lytic terminal complement complex C5b-9. Importantly, C5 blockade preserves the immunoprotective and immunoregulatory functions of early complement components.”
The study, which began June 16, will:
- assess survival in participants with COVID-19 receiving Soliris® treatment, including the efficacy of Soliris® in these patients
- characterize the overall safety of Soliris® in the treatment of COVID-19, as well as its long-term effects
- examine its pharmacokinetic and pharmacodynamics effectiveness as well as the C5 inhibition on systemic activation of complement and inflammation
As many as 100 patients are expected to participate in The Ohio State University Wexner Medical Center’s expanded access program, which could last up to 4½ months for each participant.