Opinion: Anti-TNF Therapies Need COVID-19 Trial Priority

With the world’s pharmaceutical industry turning its eyes toward finding treatments for coronavirus disease 2019 (COVID-19), authors of a commentary piece urge investigators to prioritize investigating anti–tumor necrosis factor (TNF) therapies.

“The potential of anti-TNF therapy as a treatment for COVID-19 is supported by both biological plausibility and observational clinical data,” the authors wrote. "Few current treatments under investigation have this level of supportive evidence."

Anti-TNF drugs, such as reference and biosimilar versions of infliximab, etanercept, and adalimumab molecules, are used to neutralize TNF, a cytokine signaling protein that causes inflammation related to a number of rheumatic conditions including rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, and inflammatory bowel disease (IBD).

“There is a long history of safe use of anti-TNF therapy in a diverse range of diseases, and supply is plentiful with many originator products available as well as many biosimilars,” the authors wrote. "Anti-TNF therapy now has huge potential. We need to urgently investigate its value through prioritization of clinical trial resources worldwide."

COVID-19–related inflammation is linked to elevated concentrations of TNF as well as interleukin (IL)-6 and IL-8. The authors noted that a major component leading to COVID-19–related lung deterioration is capillary leak as a result of inflammation caused by these key cytokines.

Capillary leak involves the release of fluid and proteins from tiny blood vessels into surrounding tissue, potentially leading to dangerously low blood pressure; low albumin, a protein made by the liver; and low plasma volume.

“It is therefore conceivable that anti-TNF therapy could reduce inflammation-driven capillary leak in COVID-19 and have a major impact on the need for ventilation and mortality,” wrote the authors.

Accumulating Research

Data from the SECURE-IBD registry suggested that patients with IBD who are on anti-TNF therapies and develop a COVID-19 infection have equally good or better results compared with those using other agents.

Researchers found that anti-TNF therapies were inversely associated with the composite outcome of death or hospital admission for COVID-19 (adjusted odds ratio [OR] 0.60; 95% CI, 0.38-0.96; P = .03). However, they did not affect the composite of intensive care admission, ventilation or death, and death alone.

Data from the COVID-19 Global Rheumatology Alliance registry on 600 patients with rheumatic diseases showed that anti-TNF therapy, used alone or in combination with other immunomodulatory drugs, was associated with a lower rate of hospital admission for COVID-19 (adjusted OR of 0.40; 95% CI, 0.19-0.81; P = .01) than for patients who did not use disease-modifying antirheumatic drugs.

When anti-TNF agents were used as monotherapy, the adjusted OR went down to 0.30 (95% CI, 0.11-0.79; P = .01) for hospital admissions.

A smaller trial of 77 patients with COVID-19 found that 40% and 13% those using non-TNF drugs for a pre-existing condition required ventilator support or died, respectively.

Although these trials are meaningful and important, there are many underway of all types, and patient recruitment challenges are anticipated.

Additionally, CATALYST, a randomized trial investigating the effects of a biosimilar infliximab (Remsima) in patients with COVID-19, is currently recruiting in the United Kingdom, where hospital admissions are low and accrual is expected to be slow.

A study is also ongoing at Tufts Medical Center in Boston, Massachusetts, in 17 patients and a prehospital study is planned in the United Kingdom to establish whether anti-TNF therapy can prevent milder COVID-19 cases from becoming severe.

“The potential of anti-TNF therapy as a treatment for COVID-19 is supported by both biological plausibility and observational clinical data. Few current treatments under investigation have this level of supportive evidence,” wrote the authors.

Data Limitations

The data from the SECURE-IBD and COVID-19 Global Rheumatology Alliance registries also have limitations in that comparators consist of other patients with rheumatic diseases or IBD. Those comparators may respond differently to COVID-19 due to changes in their immune system.

Also, patients with rheumatic diseases who take anti-TNF therapies likely have been on these therapies for a considerable amount of time prior to contracting COVID-19, making it hard to discern whether a first administration of anti-TNF therapy would yield the same results.

“It is therefore unknown whether the anti-TNF therapy results found in these registries are generalizable to the public,” the authors noted.

The number of current case reports on the use of anti-TNF therapies in patients with COVID-19 is small.

Reference

Robinson PC, Richard D, Tanner HL, Feldmann M. Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment. Lancet Rheumtaol. Published online September 4, 2020. doi:10.1016/ S2665-9913(20)30309-Xpubm